hairy

DEVELOPMENTAL BIOLOGY

Embryonic

The Hairy and Even-skipped protein stripes overlap extensively, but are out of phase. hairy expression extends about three cells anterior to the first (most anterior) Eve stripe, two cells anterior to the second Eve stripe, and one cell anterior to the third Eve stripe. It appears to coincide with the fourth Eve stripe (Carroll, 1988).

Expression of hairy can be detected in the stomatogastric nervous system (SNS). It is expressed already in a well defined mitotic domain at stage 5 and continues to be expressed in the SNS anlage through SNS invaginations until the time that vesicles pinch off from the epithelium. Embryos homozygous for a specific P-element insertion in hairy have extra neural cells in the ganglia of the SNS and correspondingly broader fascicles as a result. There is no pair rule phenotype resulting from the specific P-element insertion which must be due to a fortuitous hit of the P-element, affecting only the function of the gene required for neural development. As a result the role of hairy in neural development can be perceived without interference of secondary traits stemming from the pair rule requirements. Thus Hairy is thought to act as a global regulator in restricting achaete expression in proneural clusters (Forjanic, 1997).

Larval

hairy is transiently expressed in a line of cells anterior to the morphogenetic furrow as it traverses the eye disc. Both Hairy and Extramachrochaete negatively regulate the progression of the morphogenetic furrow in the developing eye (Brown, 1995).

The bristle patterning genes hairy and extramacrochaetae regulate the development of structures required for flight in Diptera

The distribution of sensory bristles on the thorax of Diptera (true flies) provides a useful model for the study of the evolution of spatial patterns. Large bristles called macrochaetes are arranged into species-specific stereotypical patterns determined via spatially discrete expression of the proneural genes achaete-scute (ac-sc). In Drosophila ac-sc expression is regulated by transcriptional activation at sites where bristle precursors develop and by repression outside of these sites. Three genes, extramacrochaetae (emc), hairy (h) and stripe (sr), involved in repression have been documented. This study demonstrates that in Drosophila, the repressor genes emc and h, like sr, play an essential role in the development of structures forming part of the flight apparatus. It was found that, in Calliphora vicina a species diverged from D. melanogaster by about 100Myr, spatial expression of emc, h and sr is conserved at the location of development of those structures. Based on these findings it is argued, first, that the role emc, h and sr in development of the flight apparatus preceded their activities for macrochaete patterning; second, that species-specific variation in activation and repression of ac-sc expression is evolving in parallel to establish a unique distribution of macrochaetes in each species (Costa, 2013).

Effects of Mutation or Deletion

Mutations that disrupt early hairy activity cause a depression of ftz expression in regions where ftz is not normally expressed. Later in development, hairy is required to suppress ectopic bristle formation on many parts of the adult body (Carroll, 1989).

It has been demonstrated that C-terminal binding protein is essential for proper embryonic segmentation by analyzing embryos lacking maternal CtBP activity. While hairy is probably not the only segmentation gene interacting with CtBP, dose-sensitive genetic interactions exist between CtBP and hairy mutations. h mutations result in a range of cuticle phenotypes from loss or fusion of adjacent denticle bands to a fusion of most of the segments ('lawn' phenotype), with the most common phenotype called the classic pair-rule phenotype that results from the loss of alternating segment-wide regions. Larvae homozygous for a strong h allele, h^7H, display the extreme 'lawn' phenotype, whereas larvae trans-heterozygous for the h^7H allele and a weaker h allele, h^12C, display the classic pair-rule phenotype. This h^7H/h^12C allelic combination was initially used to examine if reducing the CtBP dose maternally would suppress or enhance the intermediate pair-rule phenotype. P1590 was genetically recombined onto a chromosome containing the h^7H allele. Reducing the dose of CtBP maternally results in the suppression of the h^7H/h^12C mutant cuticle phenotype. Likewise, reducing the dose of CtBP maternally in the severe h^7H background suppresses the extreme lawn phenotype. No alterations in viability or phenotype of any progeny classes are observed when P1590 is trans-heterozygous with h^7H, or when the h^7H P1590 recombinant chromosome is crossed to wild-type (Poortinga, 1998).

The magnitude of segregating variation for bristle number in Drosophila exceeds that predicted from models of mutation-selection balance. To evaluate the hypothesis that genotype-environment interaction (GEI) maintains variation for bristle number in nature, the extent of GEI was quantitated for abdominal and sternopleural bristles among 98 recombinant inbred lines, derived from two homozygous laboratory strains, in three temperature environments. There is considerable GEI for both bristle traits. A genome-wide screen was conducted for quantitative trait loci (QTLs) affecting bristle number in each sex and temperature environment, using a dense (3.2-cM) marker map of polymorphic insertion sites of roo transposable elements. Nine sternopleural and 11 abdominal bristle number QTLs were detected. Significant GEI is exhibited by 14 QTLs, but there was heterogeneity among QTLs in their sensitivity to thermal and sexual environments. To further evaluate the hypothesis that GEI maintains variation for bristle number, estimates of allelic effects across environments at genetic loci affecting the traits are required. This level of resolution may be achievable for Drosophila bristle number because candidate loci affecting bristle development often map to the same location as bristle number QTL, including achaete-scute, scabrous, hairy, and Delta (Gurganus, 1998).

naked cuticle (nkd) loss-of-function clones were induced in imaginal discs and adult structures using two strong nkd alleles, nkd^7H16 and nkd^7E89, and one moderately severe allele, nkd^9G33, all of which are embryonic lethal. nkd alleles were originally generated in the genetic background of a weak allele of the pair-rule gene hairy (h¹). h¹ clones give rise to ectopic wing-vein bristles and thoracic microchaetes. Furthermore, nkd and h genetically interact: nkd, h¹/h^null is lethal, whereas h¹/h ^null is viable (A. Martinez-Arias, personal communication to Zeng, 2000). Therefore clones were generated of the strong allele nkd^7E89 from which h¹ had been removed. In many tissues where Wg signals control pattern, including the wing, thorax, abdomen, haltere and eye, phenotypically normal nkd clones are seen. h ¹, nkd^7H16, but not h ⁺, nkd^7E89 or h¹, nkd^9G33 clones give rise to a rough eye phenotype and loss of wing margin bristle phenotype that may be due to h-nkd interactions (Zeng, 2000).

Advances in medicine, agriculture, and an understanding of evolution depend on resolving the genetic architecture of quantitative traits, which is challenging since variation for complex traits is caused by multiple interacting quantitative trait loci (QTL) with small and conditional effects. hairy (h) is a QTL for Drosophila sternopleural bristle number, a model quantitative trait. Near-isoallelic lines (NIL) for the h gene region exhibit significant variation in bristle number and fail to complement a hairy mutation. Sequencing 10 h alleles from a single population has revealed 330 polymorphic sites in ~10 kb. Genotypes for 25 of these and 14 additional sites in the flanking regions were determined for the 57 NIL and associated with variation in bristle number in four genetic backgrounds. A highly significant association was found for a complicated insertion/deletion polymorphism upstream of the transcription start site. This polymorphism, present in 17.5% of the h alleles, was associated with an increase of 0.5 bristle and accounted for 31% of the genetic variance in bristle number in the NIL (Robin, 2002).

The insertion 2187in is a complicated insertion/SNP present in 17.5% of the alleles, where the common sequence ATAAAAAAA has been replaced by TATACATAGTATAGTATATATAGT. Comparison with D. simulans shows that the common sequence is the ancestral state. The presence of 2187in is associated with an increase of 0.64 sternopleural bristles across all genetic backgrounds, with no significant interactions with genetic background or sex. Differences of 0.54, 0.51, and 0.42 bristle between the in2187 and del2187 (the common sequence) alleles are significant in the homozygous NIL, NIL/h¹, and NIL/Sam genotypes, respectively; but a difference of 1.14 bristle was not significant in the chromosome 3 substitution lines. The fraction of the among-line genetic variance associated with del2187in is given by the ratio of the variance component attributable to this marker to the total among-line genetic variance for each genotype and ranged from 12% in the chromosome 3 substitution lines to 73% in the NIL/Sam heterozygotes (Robin, 2002).

It is illustrative to calculate the potential contribution of del2187in to naturally occurring variation in sternopleural bristle number in a random breeding population. This locus would account for only 1.3% of the additive genetic variance and 0.45% of the phenotypic variance. However, an additive model may not be appropriate, since in2187 appears to be dominant to del2187 (Robin, 2002).

The data illustrate how critical it is to utilize the correct density of markers, relative to historical recombination, in association study designs. In outbred populations, the power to detect associations between polymorphic molecular markers and quantitative trait phenotypes depends on the magnitude of the effect of the causal molecular variant [the quantitative trait nucleotide (QTN)], the sample size, and the strength of linkage disequilibrium between the QTN and the markers used in the association test. If the genotype of del2187in had not been determined in this sample, none of the associations would have reached the stringent level of statistical significance required to account for multiple tests. It follows that additional QTN affecting bristle number might have been revealed had the marker density been greater. Resolving which polymorphic site(s) causes variation in phenotypes will ultimately require genotyping all variable sites on large samples of alleles, to eliminate the possibility of hidden causal QTN and to detect informative recombinants. In Drosophila regions of high recombination and polymorphism, this requirement currently restricts the utility of linkage disequilibrium mapping in outbred populations to mapping QTN within candidate genes. While h was a clear candidate gene affecting bristle number, many QTL map to regions containing no obvious candidate genes. With the ultimate availability of stocks containing targeted disruptions of all known and predicted genes in Drosophila and other model organisms, quantitative complementation of QTL alleles to mutations of all genes in the region to which QTL map provides a reliable, rapid, and cost-effective method for nominating candidate genes for further study (Robin, 2002).

This is one of a growing number of examples indicating that variation in noncoding regions is likely to be responsible for quantitative genetic variation, which in turn can motivate functional studies to define regulatory motifs (in this case, regulatory sites for expression of h in the PNS). Intermediate frequency polymorphisms associated with quantitative traits are not likely to be maintained by mutation-selection balance, further motivating large-scale future studies with new designs to detect hallmarks of positive or balancing selection at this locus (Robin, 2002).

Formation of tubes of the correct size and shape is essential for viability of most organisms, yet little is understood of the mechanisms controlling tube morphology. A new allele of hairy has been identified in a mutagenesis screen. hairy mutations cause branching and bulging of the normally unbranched salivary tube, in part through prolonged expression of huckebein (hkb). Hkb controls polarized cell shape change and apical membrane growth during salivary cell invagination via two downstream target genes, crumbs (crb), a determinant of the apical membrane, and klarsicht (klar), which mediates microtubule-dependent organelle transport. In invaginating salivary cells, crb and klar mediate growth and delivery of apical membrane, respectively, thus regulating the size and shape of the salivary tube (Myat, 2002).

Traditional screens aiming at identifying genes regulating development have relied on mutagenesis. A new gene has been identified involved in bristle development, identified through the use of natural variation and selection. Drosophila melanogaster bears a pattern of 11 macrochaetes per heminotum. From a population initially sampled in Marrakech, a strain was selected for an increased number of thoracic macrochaetes. Using recombination and single nucleotide polymorphisms, the factor responsible was mapped to a single locus on the third chromosome, poils au dos (French for 'hairy back'), that encodes a zinc-finger-ZAD protein. The original, as well as new, presumed null alleles of poils au dos are associated with ectopic achaete-scute expression that results in the additional bristles. This suggests a possible role for Poils au dos as a repressor of achaete and scute. Ectopic expression appears to be independent of the activity of known cis-regulatory enhancer sequences at the achaete–scute complex that mediate activation at specific sites on the notum. The target sequences for Poils au dos activity were mapped to a 14 kb region around scute. In addition, pad has been shown to interact synergistically with the repressor hairy and with Dpp signaling in posterior and anterior regions of the notum, respectively (Gibert, 2005).

The generalized increase in ac-sc expression in pad mutants suggests that pad is involved in the repression of ac-sc. Interactions between pad and other known repressors of ac-sc were tested. pad¹ interacts moderately with emc^pel and very strongly with hairy¹. In h¹ homozygotes grown at 18°C, ectopic bristles are occasionally found anterior to the aDC, whereas none were seen at 25°C. In h¹ pad¹ homozygotes, many ectopic bristles were observed at 25°C at positions where none were seen in either of the single mutants. These include DC bristles closer to the thoracic midline and additional bristles between the anterior and posterior scutellars. Interestingly, most of these ectopic bristles are located in the posterior half of the notum whereas the visible effect of pad alone is in the anterior part of the notum (Gibert, 2005).

The bHLH transcription factor, hairy, refines the terminal cell fate in the Drosophila embryonic trachea

The pair-rule gene, hairy, encodes a basic helix-loop-helix transcription factor and is required for patterning of the early Drosophila embryo and for morphogenesis of the embryonic salivary gland. Although hairy was shown to be expressed in the tracheal primordia and in surrounding mesoderm, whether hairy plays a role in tracheal development is not known. This study reports that hairy is required for refining the terminal cell fate in the embryonic trachea and that hairy's tracheal function is distinct from its earlier role in embryonic patterning. In hairy mutant embryos where the repressive activity of hairy is lost due to lack of its co-repressor binding site, extra terminal cells are specified in the dorsal branches. hairy was shown to function in the muscle to refine the terminal cell fate to a single cell at the tip of the dorsal branch by limiting the expression domain of branchless (bnl), encoding the FGF ligand, in surrounding muscle cells. Abnormal activation of the Bnl signaling pathway in hairy mutant tracheal cells is exemplified by increased number of dorsal branch cells expressing Bnl receptor, Breathless (Btl) and Pointed, a downstream target of the Bnl/Btl signaling pathway. hairy genetically interacts with bnl in TC fate restriction, and overexpression of bnl in a subset of the muscle surrounding tracheal cells phenocopies the hairy mutant phenotype. These studies demonstrate a novel role for Hairy in restriction of the terminal cell fate by limiting the domain of bnl expression in surrounding muscle cells such that only a single dorsal branch cell becomes specified as a terminal cell. These studies provide the first evidence for Hairy in regulation of the FGF signaling pathway during branching morphogenesis (Zhan, 2010).

To date hairy function in epithelial morphogenesis is limited to a previous study on hairy's role in the regulation of apical membrane growth during embryonic salivary gland development. The current study demonstrate a novel function for hairy in refinement of the terminal cell fate to a single cell at the tip of the dorsal branch through restriction of bnl expression domains in muscle cells surrounding tracheal cells. Due to the strong requirement for hairy in early embryonic patterning, it was necessary to distinguish hairy function in tracheal development from its earlier patterning role. Thus, this analysis of hairy function in the trachea was focused on mutations that did not perturb segmentation of the embryo. h⁴⁷ mutant embryos had no patterning defect, and yet, extra TCs were specified. h^ACT, which not only lacks the WRPW motif but also contains the transcriptional activation domain of VP16 induces ectopic expression of target genes when expressed in the late blastoderm stage, the time when endogenous Hairy is expressed and is active. Expression of h^ACT in mid-embryogenesis, prior to specification of the terminal cell fate led to ectopic expression of bnl in muscle cells and specification of extra TCs. Since h^ACT was induced after patterning of the early embryo was complete, there were no segmentation defects in h^ACT-expressing embryos and yet, extra TCs were specified. Similar to h^ACT, in h⁶⁷⁴ mutant embryos with no segmentation defect, bnl expression domain was expanded and extra TCs were specified. Since, h⁶⁷⁴, like h^ACT, lacks the C-terminal co-repressor binding WRPW tetrapeptide it is possible that the Hairy mutant protein of h⁶⁷⁴ embryos also acts as an activator and induces expression of downstream target genes. Thus, the h⁴⁷, h⁶⁷⁴and h^ACT mutant embryos which are segmented properly and yet show specification of extra TCs in the tracheal dorsal branches provide evidence that hairy's role in early patterning and in tracheal development are indeed distinct (Zhan, 2010).

In addition to a role for hairy in refinement of the terminal cell fate through regulation of bnl expression in muscle cells, evidence is provided that hairy and bnl act antagonistically to regulate terminal branch lumen length. These studies provide the first evidence for a role for bnl in tracheal lumen size control. Although hairy mutant tracheal cells invaginated completely, they did so in an uncoordinated manner compared to wild-type. Thus, hairy function is required at multiple stages of tracheal development (Zhan, 2010).

The data support a model where Hairy in the somatic muscle, normally refines the spatial expression of bnl in the muscle cells that are in close proximity to the migrating tracheal branches, such that only a single cell at the tip of each dorsal branch becomes specified as the terminal cell. Upon loss of Hairy's repressive activity, bnl expression expands in the muscle cells and abnormally activates the bnl/btl signaling pathway, such that extra TCs become specified. These data do not suggest whether bnl is a direct or indirect transcriptional target of Hairy; future studies will distinguish between these two possibilities. It is also possible that Hairy regulates bnl/btl signaling and TC specification via mechanisms other than control of bnl expression. For example, it was recently shown that in the developing tracheal air sac of Drosophila larvae, matrix metalloprotease Mmp2 spatially restricts FGF signaling. Thus, hairy may modulate the extent of bnl/btl signaling in tracheal cells in a post-translational manner as well (Zhan, 2010).

The role of the bHLH protein hairy in morphogenetic furrow progression in the developing Drosophila eye

In Drosophila eye development, a wave of differentiation follows a morphogenetic furrow progressing across the eye imaginal disc. This is subject to negative regulation attributed to the HLH repressor proteins Hairy and Extramacrochaete. Recent studies identify negative feedback on the bHLH gene daughterless as one of the main functions of extramacrochaete. This study assessed the role of hairy in relation to daughterless and other HLH genes. Hairy was not found to regulate the expression of Daughterless, Extramacrochaete or Atonal, and Hairy expression was largely unregulated by these other genes. Null alleles of hairy did not alter the rate or pattern of differentiation, either alone or in the absence of Extramacrochaete. These findings question whether hairy is an important regulator of the progression of retinal differentiation in Drosophila, alone or redundantly with extramacrochaete (Bhattacharya, 2012).

The morphogenetic furrow moves anteriorly across the eye disc under the positive influence of Hh and Dpp. The forward progression of differentiation is a consequence of the positive activation of Ato expression as well as the parallel repression of Emc, which results in elevated levels of the heterodimer partner of Ato, Da. Hh and Dpp also affect the cell cycle, the shapes of cells in the morphogenetic furrow, the expression of retinal determination genes, and the sizes of nucleoli, although it remains to be determined whether these other processes contribute directly to neural differentiation (Bhattacharya, 2012).

This paper addresses hairy, a potential barrier to morphogenetic furrow movement. Hairy protein is expressed through much of the eye disc anterior to the morphogenetic furrow, and is downregulated sharply at the time that Atonal becomes active. Although clones of hairy null mutations do not affect eye differentiation, it has been thought that hairy acts along with emc. so that emc hypomorphs that have no effect on the morphogenetic furrow progression alone do speed up the furrow in combination with hairy null mutations. It has been proposed that Hairy is a marker of a 'preproneural state', in which the presence of Hairy helps restrain incipient neurogenesis (Bhattacharya, 2012).

If hairy acts redundantly with emc, this might be explained by convergence on common targets, since both encode transcriptional repressors. This study found, however, no noticeable effect of hairy null alleles on Da expression, Emc expression, or Ato expression. In addition, h emc double mutant clones appeared to have no additional effect on Da expression from that seen in emc clones. Since no obvious role for hairy in the expression of these genes was detected, the progression of the morphogenetic furrow was measured directly. Although differentiation progresses faster through cells null for emc than through wild type cells, removing hairy had no further effect on morphogenetic furrow progression. These findings provide no evidence that hairy acted redundantly with emc, since it did not regulate morphogenetic furrow progression or target gene expression when emc function was removed, implying that hairy function was not sufficient to compensate even partially for the absence of emc. In fact, a hairy null mutation has no discernible effect on the morphogenetic furrow in either the presence or absence of emc. There may be a small role for emc in regulating Hairy expression, such that Hairy is repressed slightly faster in the absence of emc, but even the complete absence of hairy has no effect on furrow progression, either in the presence or absence of emc. In conjunction with experiments in which Hairy did not affect morphogenetic furrow progression when over-expressed, these findings challenge the model that Hairy regulates morphogenetic furrow progression (Bhattacharya, 2012).

The role for hairy in regulating morphogenetic furrow progression was suggested because hairy antagonizes neurogenesis in other imaginal discs, and because hairy mutations enhanced the phenotype of the emc¹ mutant allele. In addition, failure to downregulate Hairy at the morphogenetic furrow correlates with reduced differentiation in a number of mutant genotypes. The neurogenic phenotype of hairy in other imaginal discs depends on Hairy binding to the enhancer of achaetae. Since achaetae is not expressed or functional during morphogenetic furrow progression, these data offer no basis for predicting hairy function in the eye (Bhattacharya, 2012).

Enhancement of the emc¹ allele, but not the emc^AP6 null allele, could be explained if hairy contributed to emc function in some way, so that hairy function can mitigate partial loss of emc function by increasing the effectiveness of the remaining Emc protein, but would not affect the emc null phenotype. The emc¹mutant allele encodes a Val-to-Glu substitution in the HLH domain, which would be expected to interfere with heterodimer formation by Emc¹ protein, consistent with a hypomorphic phenotype. No evidence was found that hairy contributed to the expression of Emc or to Emc function as a negative regulator of da. Another possibility is that Hairy protein might act through distinct mechanisms in addition to binding to specific DNA sequences. The E(spl) proteins, which contain similar domains to Hairy, can also repress gene expression when targeted to particular genes by protein-protein interactions. It has not been tested whether Hairy might exhibit similar protein-protein interactions. It is also reported that the Chicken Id protein, a homolog of Emc, interacts directly with Hes1, a homolog of Hairy. Thus far, however, Drosophila Hairy is not known to heterodimerize with Emc or any of its proneural gene targets. It is possible that Hairy might regulate da transcription in a subtle way only revealed in the emc¹ backgrounds. For example, Hairy repression of da transcription might be redundant in the presence of wild type emc, and not sufficient to impact da autoregulation in the complete absence of Emc. Detailed information concerning the thresholds of da transcription under different conditions would be required to assess this model (Bhattacharya, 2012).

The Hairy expression ahead of the morphogenetic furrow certainly seems to provide a marker of an early stage of eye development. Consistent with this, retention of Hairy expression in mutant genotypes correlates with diminished retinal differentiation. The findings of this study indicate that, contrary to previous models, any contribution of Hairy to morphogenetic furrow progression is quite limited, and there is little evidence to connect it with emc. The possibility remains that hairy may function in a subtle way, perhaps redundantly with other genes, or affect processes other than furrow progression, particularly since many questions remain to be resolved concerning the transcriptional regulation of eye development, such as how ato expression is initiated as the furrow progresses, or all the mechanisms by which the retinal determination genes contribute to eye development. It is also possible that laboratory conditions conceal the contribution of the hairy gene in eye development, as has been suggested for regulatory pathways that are thought to contribute temperature stability in variable environments (Bhattacharya, 2012).

Abed, M., et al. (2011). Degringolade, a SUMO-targeted ubiquitin ligase, inhibits Hairy/Groucho-mediated repression. EMBO J. 30(7): 1289-301. PubMed Citation: 21343912

Alper, S. and Kenyon, C. (2001). REF-1, a protein with two bHLH domains, alters the pattern of cell fusion in C. elegans by regulating Hox protein activity. Development 128(10): 1793-804. 11311160

Andoniadou, C. L., et al. (2011). HESX1- and TCF3-mediated repression of Wnt/?-catenin targets is required for normal development of the anterior forebrain. Development 138(22): 4931-42. PubMed Citation: 22007134

Andrioli, L. P., Digiampietri, L. A., de Barros, L. P. and Machado-Lima, A. (2012). Huckebein is part of a combinatorial repression code in the anterior blastoderm. Dev. Biol. 361(1): 177-85. PubMed Citation: 22027434

Androutsellis-Theotokis, A., Leker, R. R., Soldner, F., Hoeppner, D. J., Ravin, R., Poser, S. W., Rueger, M. A., Bae, S. K., Kittappa, R., and McKay, R. D. (2006). Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 442: 823-826. Medline abstract: 16799564

Aronson, B. D., et al. (1997). Groucho-dependent and -independent repression activities of Runt domain proteins. Mol. Cell. Biol. 17(9): 5581-5587. PubMed Citation: 9271433

Aujla, P. K., et al. (2011). The Notch effector gene Hes1 regulates migration of hypothalamic neurons, neuropeptide content and axon targeting to the pituitary. Dev. Biol. 353(1): 61-71. PubMed Citation: 21354131

Barolo, S. and Levine, M. (1997). hairy mediates dominant repression in the Drosophila embryo. EMBO J. 16: 2883-91. PubMed Citation: 9184232

Bae, S.-K., et al. (2000). The bHLH gene Hes6, an inhibitor of Hes1, promotes neuronal differentiation. Development 127: 2933-2943. PubMed Citation: 10851137

Bae, Y.-K., Shimizu, T. and Hibi, M. (2005). Patterning of proneuronal and inter-proneuronal domains by hairy- and enhancer of split-related genes in zebrafish neuroectoderm. Development 132(6): 1375-85.15716337

Bhattacharya, A. and Baker, N. E. (2012). The role of the bHLH protein hairy in morphogenetic furrow progression in the developing Drosophila eye. PLoS One 7: e47503. PubMed ID: 23118874

Bai, G., et al. (2007). Id sustains Hes1 expression to inhibit precocious neurogenesis by releasing negative autoregulation of Hes1. Dev Cell. 13(2): 283-97. PubMed citation: 17681138

Bally-Cuif, L., et al. (2000). Coregulation of anterior and posterior mesendodermal development by a hairy-related transcriptional repressor. Genes Dev. 14: 1664-1677. PubMed Citation: 10887160

Baonza, A. and Freeman, M. (2001). Notch signaling and the initiation of neural development in the Drosophila eye. Development 128: 3889-3898. 11641214

Barry, K. C., et al. (2011). The Drosophila STUbL protein Degringolade limits HES functions during embryogenesis. Development 138(9): 1759-69. PubMed Citation: 21486924

Beatus, P., et al. (1999). The Notch 3 intracellular domain represses Notch 1-mediated activation through Hairy/Enhancer of split (HES) promoters. Development 126: 3925-3935. PubMed Citation: 10433920

Beatus, P., et al. (2001). The origin of the ankyrin repeat region in Notch intracellular domains is critical for regulation of HES promoter activity. Mech. of Dev. 104: 3-20. 11404076

Berberoglu M. A., Dong Z., Mueller T. and Guo S. (2009). fezf2 expression delineates cells with proliferative potential and expressing markers of neural stem cells in the adult zebrafish brain. Gene Expr. Patterns 9: 411-422. PubMed Citation: 19524703

Bessa, J., et al. (2002). Combinatorial control of Drosophila eye development by Eyeless, Homothorax, and Teashirt. Genes Dev. 16: 2415-2427. 12231630

Bessho, Y., et al. (2001). Dynamic expression and essential functions of Hes7 in somite segmentation. Genes Dev. 15: 2642-2647. 11641270

Bessho, Y., et al. (2003). Periodic repression by the bHLH factor Hes7 is an essential mechanism for the somite segmentation clock. Genes Dev. 17: 1451-1456. 12783854

Bianchi-Frias, D., et al. (2004). Hairy transcriptional repression targets and cofactor recruitment in Drosophila. PLoS Biol. 2(7): E178. 15252443

Brown, N.L., Sattler, C.A., Paddock, S.W. and Carroll, S.B. (1995). hairy and emc negatively regulate morphogenetic furrow progresssion in the Drosophila eye. Cell 80: 879-87. PubMed Citation: 7697718

Bullock, S. L. and Ish-Horowicz, D. (2001). Conserved signals and machinery for RNA transport in Drosophila oogenesis and embryogenesis. Nature 414(6864): 611-6. 11740552

Bullock, S. L., Zicha, D. and Ish-Horowicz, D., et al. (2003). The Drosophila hairy RNA localization signal modulates the kinetics of cytoplasmic mRNA transport. EMBO J. 22: 2484-2494. 12743042

Bullock, S. L., et al. (2004). Differential cytoplasmic mRNA localisation adjusts pair-rule transcription factor activity to cytoarchitecture in dipteran evolution. Development 131: 4251-4261. 15280214

Carroll, S.B., Laughon, A. and Thallay, B.S. (1988). Expression, function and regulation of the hairy segmentation protein in the Drosophila embryo. Genes Dev. 2: 883-90. PubMed Citation: 3209072

Carroll, S.B. and White, J.S. (1989). The role of the hairy gene during Drosophila morphogenesis: stripes in imaginal discs. Genes Dev. 3: 305-316FlyBase record

Cau, E., et al. (2000). Hes genes regulate sequential stages of neurogenesis in the olfactory epithelium. Development 127: 2323-2332. PubMed Citation: 10804175

Chen, H., et al. (1997). Conservation of the Drosophila lateral inhibition pathway in human lung cancer: a hairy-related protein (HES-1) directly represses achaete-scute homolog-1 expression. Proc. Natl. Acad. Sci. 94 (10): 5355-5360. PubMed Citation: 9144241

Costa, M., Calleja, M., Alonso, C. R. and Simpson, P. (2013). The bristle patterning genes hairy and extramacrochaetae regulate the development of structures required for flight in Diptera. Dev Biol. [Epub ahead of print] PubMed ID: 24384389

Cunliffe, V. T. (2004). Histone deacetylase 1 is required to repress Notch target gene expression during zebrafish neurogenesis and to maintain the production of motoneurones in response to hedgehog signalling. Development 131: 2983-2995. 15169759

Damen, W. G. M., Weller, M. and Tautz, D. (2000). Expression patterns of hairy, even-skipped, and runt in the spider Cupiennius salei imply that these genes were segmentation genes in a basal arthropod. Proc. Natl. Acad. Sci. 97: 4515-4519. PubMed Citation: 10781054

Davis, R. L., et al. (2001). Molecular targets of vertebrate segmentation: Two mechanisms control segmental expression of Xenopus hairy2 during somite formation. Dev. Cell 1: 553-565. 11703945

Dawson, S. R., et al. (1995). Specificity for the hairy/enhancer of split basic helix-loop-helix (bHLH) proteins maps outside the bHLH domain and suggests two separable modes of transcriptional repression. Mol. Cell Biol. 15: 6923-6931. PubMed Citation: 8524259

Deisseroth, K., et al. (2004). Excitation-neurogenesis coupling in adult neural stem/progenitor cells. Neuron 42: 535-552. 15157417

de la Calle-Mustienes, E., et al. (2002). Xiro homeoproteins coordinate cell cycle exit and primary neuron formation by upregulating neuronal-fate repressors and downregulating the cell-cycle inhibitor XGadd45-gamma. Mech. Dev. 119: 69-80. 12385755

Deneen, B., et al. (2006). The transcription factor NFIA controls the onset of gliogenesis in the developing spinal cord. Neuron 52(6): 953-68. PubMed Citation: 17178400

Dienstbier, M., Boehl, F., Li, X. and Bullock, S. L. (2009). Egalitarian is a selective RNA-binding protein linking mRNA localization signals to the dynein motor. Genes Dev. 23(13): 1546-58. PubMed Citation: 19515976

Doetzlhofer, A., et al. (2009). Hey2 regulation by FGF provides a Notch-independent mechanism for maintaining pillar cell fate in the organ of Corti. Dev. Cell 16(1): 58-69. PubMed Citation: 19154718

Dong, Y., et al. (2010). RBPjkappa-dependent Notch signaling regulates mesenchymal progenitor cell proliferation and differentiation during skeletal development. Development 137(9): 1461-71. PubMed Citation: 20335360

Esni, F., et al. (2004). Notch inhibits Ptf1 function and acinar cell differentiation in developing mouse and zebrafish pancreas. Development 131: 4213-4224. 15280211

Espinas, M. L., Canudas, S., Fanti, L., Pimpinelli, S., Casanova, J. and Azorin, F. (2000). The GAGA factor of Drosophila interacts with SAP18, a Sin3-associated polypeptide. EMBO Rep. 1: 253-259. PubMed Citation: 11256608

Feder, J. N., et al. (1994) Genomic cloning and chromosomal localization of HRY, the human homolog to the Drosophila segmentation gene, hairy. Genomics 20: 56-61. PubMed Citation: 8020957

Fisher, A. L., Ohsako, S. and Caudy, M. (1996).The WRPW motif of the hairy-related basic helix-loop-helix repressor proteins acts as a 4-amino-acid transcription repression and protein-protein interaction domain. Mol. Cell. Biol. 16: 2670-2677. PubMed Citation: 8649374

Forjanic, J. P., et al. (1997). Genetic analysis of stomatogastric nervous system development in Drosophila using enhancer trap lines. Development 186: 139-154. PubMed Citation: 9205135

Friedmann, D. R. and Kovall, R. A. (2010). Thermodynamic and structural insights into CSL-DNA complexes. Protein Sci. 19(1): 34-46. PubMed Citation: 19866488

Fu, W. and Baker, N. E. (2003). Deciphering synergistic and redundant roles of Hedgehog, Decapentaplegic and Delta that drive the wave of differentiation in Drosophila eye development. Development 130: 5229-5239. 12954721

Fukada, S., et al. (2011). Hesr1 and Hesr3 are essential to generate undifferentiated quiescent satellite cells and to maintain satellite cell numbers. Development 138(21): 4609-19. PubMed Citation: 21989910

Furukawa, T., et al. (2000). rax, Hes1, and notch1 promote the formation of Müller glia by postnatal retinal progenitor cells. Neuron 26: 383-394. PubMed Citation: 10839357

Gajewski, M., et al. (2003). Anterior and posterior waves of cyclic her1 gene expression are differentially regulated in the presomitic mesoderm of zebrafish. Development 130: 4269-4278. 12900444

Glavic, A., et al. (2004). Interplay between Notch signaling and the homeoprotein Xiro1 is required for neural crest induction in Xenopus embryos. Development 131: 347-359. 14681193

Gao, X., et al. (2001). HES6 acts as a transcriptional repressor in myoblasts and can induce the myogenic differentiation program. J. Cell Biol. 154: 1161-1172. 11551980

Geling, A., et al. (2003). bHLH transcription factor Her5 links patterning to regional inhibition of neurogenesis at the midbrain-hindbrain boundary. Development 130: 1591-1604. 12620984

Geling, A., et al. (2004). Her5 acts as a prepattern factor that blocks neurogenin1 and coe2 expression upstream of Notch to inhibit neurogenesis at the midbrain-hindbrain boundary. Development 131: 1993-2006. 15056616

Gibert, J. M., Marcellini, S., David, J. R., Schlotterer, C. and Simpson, P. (2005). A major bristle QTL from a selected population of Drosophila uncovers the zinc-finger transcription factor Poils-au-dos, a repressor of achaete-scute. Dev. Biol. 288(1): 194-205. 16216235

Goodfellow, H., Krejcí, A., Moshkin, Y., Verrijzer, C. P., Karch, F. and Bray, S. J. (2007). Gene-specific targeting of the histone chaperone asf1 to mediate silencing. Dev. Cell 13(4): 593-600. PubMed citation: 17925233

Greenwood, S. and Struhl, G. (1999). Progression of the morphogenetic furrow in the Drosophila eye: the roles of Hedgehog, Decapentaplegic and the Raf pathway. Development 126: 5795-5808. PubMed Citation: 10572054

Gurganus, M. C., et al. (1998). Genotype-environment interaction at quantitative trait loci affecting sensory bristle number in Drosophila melanogaster. Genetics 149(4): 1883-1898. PubMed Citation: 9691044

Gutjahr, T. Frei, E. and Noll, M. (1993). Complex regulation of early paired expression: initial activation by gap genes and pattern modulation by pair-rule genes. Development 117: 609-23. PubMed Citation: 8330531

Hader, T., et al. (1998). Activation of posterior pair-rule stripe expression in response to maternal caudal and zygotic knirps activities. Mech. Dev. 71(1-2): 177-186. PubMed Citation: 9507113

Hans, S., Scheer, N., Ried, I., v. Weizsäcker, E., Blader, P. and Campos-Ortega, J. A. (2004). her3, a zebrafish member of the hairy-E(spl) family, is repressed by Notch signalling. Development 131: 2957-2969. 15169758

Hartmann, C., et al. (1994). A two-step mode of stripe formation in the Drosophila blastoderm requires interactions among primary pair rule genes. Mech Dev 45: 3-13. PubMed Citation: 8186146

Hatakeyama, J., et al. (2004). Hes genes regulate size, shape and histogenesis of the nervous system by control of the timing of neural stem cell differentiation. Development 131: 5539-5550. 15496443

Hays, R., et al. (1999). Patterning of Drosophila leg sensory organs through combinatorial signaling by Hedgehog, Decapentaplegic and Wingless. Development 126: 2891-2899. PubMed Citation: 10357933

Henry, C. A., et al. (2002). Two linked hairy/Enhancer of split-related zebrafish genes, her1 and her7, function together to refine alternating somite boundaries. Development 129: 3693-3704. 12117818

Hirata, H., et al. (2001). Hes1 and Hes3 regulate maintenance of the isthmic organizer and development of the mid/hindbrain. EMBO J. 20: 4454-4466. 11500373

Hojo, M., et al. (2000). Glial cell fate specification modulated by the bHLH gene Hes5 in mouse retina. Development 127: 2515-2522. PubMed Citation: 10821751

Holley, S. A., Geisler, R. and Nusslein-Volhard, C. (2000). Control of her1 expression during zebrafish somitogenesis by a Delta-dependent oscillator and an independent wave-front activity. Genes Dev. 14: 1678-1690. PubMed Citation: 10887161

Holley, S. A., et al. (2002). her1 and the notch pathway function within the oscillator mechanism that regulates zebrafish somitogenesis. Development 129: 1175-1183. 11874913

Ishibashi, M., et al. (1994). Persistent expression of helix-loop-helix factor HES-1 prevents mammalian neural differentiation in the central nervous system. EMBO J. 13: 1799-805. PubMed Citation: 7909512

Ishibashi, M., et al. (1995). Targeted disruption of mammalian hairy and Enhancer of split homolog-1 (HES-1) leads to up-regulation of neural helix-loop-helix factors, premature neurogenesis, and severe neural tube defects. Genes Dev. 9: 3136-3148. PubMed Citation: 8543157

Ishikawa, A., et al. (2004). Mouse Nkd1, a Wnt antagonist, exhibits oscillatory gene expression in the PSM under the control of Notch signaling. Mech. Dev. 121(12): 1443-53. 15511637

Ishimatsu, K., Takamatsu, A. and Takeda, H. (2010). Emergence of traveling waves in the zebrafish segmentation clock. Development 137(10): 1595-9. PubMed Citation: 20392739

Jarriault, S., et al. (1998). Delta-1 activation of Notch-1 signaling results in HES-1 transactivation. Mol. Cell. Biol. 18(12): 7423-7431. PubMed Citation: 9819428

Jennings, B. H., Wainwright, S. M. and Ish-Horowicz, D. (2008). Differential in vivo requirements for oligomerization during Groucho-mediated repression. EMBO Rep. 9(1): 76-83. PubMed Citation: 18034187

Jeong J. Y., et al. (2007). Patterning the zebrafish diencephalon by the conserved zinc-finger protein Fezl. Development 134: 127-136. PubMed Citation: 17164418

Jiménez, G., Pinchin, S. M. and Ish-Horowicz, D. (1996). In vivo interactions of the Drosophila Hairy and Runt transcriptional repressors with target promoters. EMBO J. 7088-7098. PubMed Citation: 9003784

Joshi, M., Buchanan, K. T., Shroff, S. and Orenic, T. V. (2006). Delta and Hairy establish a periodic prepattern that positions sensory bristles in Drosophila legs. Dev. Biol. 293(1): 64-76. 16542648

Jouve, C., et al. (2000). Notch signaling is required for cyclic expression of the hairy-like gene HES1 in the presomitic mesoderm. Development 127: 1421-1429. PubMed Citation: 10704388

Ju, B. G., et al. (2004). Activating the PARP-1 sensor component of the Groucho/ TLE1 corepressor complex mediates a CaMKinase II-dependent neurogenic gene activation pathway. Cell 119: 815-829. 15607978

Kahali, B., Trott, R., Paroush, Z., Allada, R., Bishop, C. P. and Bidwai, A. P. (2008). Drosophila CK2 phosphorylates Hairy and regulates its activity in vivo. Biochem. Biophys. Res. Commun. 373: 637-642. PubMed Citation: 18601910

Kawamura, A., Koshida, S., Hijikata, H., Sakaguchi, T., Kondoh, H. and Takada, S. (2005). Zebrafish hairy/enhancer of split protein links FGF signaling to cyclic gene expression in the periodic segmentation of somites. Genes Dev. 19(10): 1156-61. 15905406

Kim, H. K. and Siu, G. (1998). The Notch pathway intermediate HES-1 silences CD4 gene expression. Mol. Cell. Biol. 18(12): 7166-7175

Kobayashi, T., Mizuno, H., Imayoshi, I., Furusawa, C., Shirahige, K., Kageyama, R. (2009). The cyclic gene Hes1 contributes to diverse differentiation responses of embryonic stem cells. Genes Dev. 23(16): 1870-5. PubMed Citation: 19684110

Kokubo, H., et al. (2005). Mouse hesr1 and hesr2 genes are redundantly required to mediate Notch signaling in the developing cardiovascular system. Dev. Biol. 278: 301-309. 15680351

Kokubo, H., et al. (2007). Hesr1 and Hesr2 regulate atrioventricular boundary formation in the developing heart through the repression of Tbx2. Development 134: 747-755. Medline abstract: 17259303

Kondo, T. and Raff, M. (2000). Basic helix-loop-helix proteins and the timing of oligodendrocyte differentiation. Development 127: 2989-2998.

Koyano-Nakagawa, N., et al. (2000). Hes6 acts in a positive feedback loop with the neurogenins to promote neuronal differentiation. Development 127: 4203-4216

Kubo, F. and Nakagawa, S. (2009). Hairy1 acts as a node downstream of Wnt signaling to maintain retinal stem cell-like progenitor cells in the chick ciliary marginal zone. Development 136(11): 1823-33. PubMed Citation: 19386663

Kwon, C., et al. (2004). Opposing inputs by Hedgehog and Brinker define a stripe of hairy expression in the Drosophila leg imaginal disc. Development 131: 2681-2692. 15128656

Lai, E. and Posakony, J. (1997). The Bearded box, a novel 3' UTR sequence motif, mediates negative post-transcriptional regulation of Beard. PubMed Citation: ed and Enhancer of split Complex gene expression. Development 124(23): 4847-4856. PubMed Citation: 9428421

Lamar, E. and Kintner, C. (2005). The Notch targets Esr1 and Esr10 are differentially regulated in Xenopus neural precursors. Development 132(16): 3619-30. 16077089

Langeland, J. A., et al. (1994). Positioning adjacent pair-rule stripes in the posterior Drosophila embryo. Development 120: 2945-2955. PubMed Citation: 7607084

La Rosee, A., et al. (1997). Mechanism and Bicoid-dependent control of hairy stripe 7 expression in the posterior region of the Drosophila embryo. EMBO J. 16(14): 4403-4411. PubMed Citation: 9250684

La Rosee-Borggreve, E., et al. (1999). hairy stripe 7 element mediates activation and repression in response to different domains and levels of Kruppel in the Drosophila embryo. Mech. of Dev. 89: 133-140. PubMed Citation: 10559488.

Lai, E. C. and Posakony, J. W. (1998). Regulation of Drosophila neurogenesis byRNA:RNA duplexes? Cell 93: 1103-1104. PubMed Citation: 9657143

Latimer, A. J., et al. (2002). Delta-Notch signaling induces hypochord development in zebrafish. Development 129: 2555-2563. 12015285

Li, M. and Arnosti, D. N. (2011). Long- and short-range transcriptional repressors induce distinct chromatin states on repressed genes. Curr. Biol. 21: 406-12. PubMed Citation: 21353562

Lobe, C. G. (1997). Expression of the helix-loop-helix factor, Hes3, during embryo development suggests a role in early midbrain-hindbrain patterning. Mech. Dev. 62 (2): 227-237. PubMed Citation: 9152013

Lopez, S. L., et al. (2005). The Notch-target gene hairy2a impedes the involution of notochordal cells by promoting floor plate fates in Xenopus embryos. Development 132(5): 1035-46.15689375

Martinez, C. A. and Arnosti. D. N. (2008). Spreading of a corepressor linked to action of long-range repressor hairy. Mol. Cell. Biol. 28(8): 2792-802. PubMed Citation: 18285466

Matter-Sadzinski, L., et al. (2005). A bHLH transcriptional network regulating the specification of retinal ganglion cells. Development 132(17): 3907-21. 16079155

Matyash, A., et al. (2009). SAP18 promotes Krüppel-dependent transcriptional repression by enhancer-specific histone deacetylation. J. Biol. Chem. 284(5): 3012-20. PubMed Citation: 19049982

McGregor, A. P., et al. (2008). Wnt8 is required for growth-zone establishment and development of opisthosomal segments in a spider. Curr. Biol. 18: 1619-1623. PubMed Citation: 18926703

McLarren, K. W., et al. (2000). The mammalian basic helix loop helix protein HES-1 binds to and modulates the transactivating function of the runt-related factor Cbfa1. J. Biol. Chem. 275(1): 530-8. PubMed Citation: 10617648

Miller, S. W., Rebeiz, M., Atanasov, J. E. and Posakony, J. W. (2014). Neural precursor-specific expression of multiple Drosophila genes is driven by dual enhancer modules with overlapping function. Proc Natl Acad Sci U S A 111(48):17194-9. PubMed ID: 25404315

Minguillón, C., et al. (2003}. The amphioxus Hairy family: differential fate after duplication. Development 130: 5903-5914. 14561632

Müller, M., Weizäcker, E. v. and Campos-Ortega, J. A. (1996). Expression domains of a zebrafish homologue of the Drosophila pair-rule gene hairy corresponding to primordia of alternating somites. Development 122 2071-78. PubMed Citation: 8681788

Molloy, D. P., et al. (2001). Structural determinants outside the PXDLS sequence affect the interaction of adenovirus E1A, C-terminal interacting protein and Drosophila repressors with C-terminal binding protein. Biochim. Biophys. Acta. 1546(1): 55-70. 11257508

Morimura, T., Goitsuka, R., Zhang, Y., Saito, I., Reth, M. and Kitamura, D. (2000). Cell cycle arrest and apoptosis induced by Notch1 in B cells. J. Biol. Chem. 275(47): 36523-31. 10967117

Moriyama, M., et al. (2008). Multiple roles of Notch signaling in the regulation of epidermal development. Dev. Cell 14(4): 594-604. PubMed Citation: 18410734

Mukhopadhyay, M., et al. (2001). Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse. Developmental Cell 1: 423-434. PubMed Citation: 1170295

Myat, M. M. and Andrew, D. J. (2002). Epithelial tube morphology is determined by the polarized growth and delivery of apical membrane. Cell 111(6): 879-91. 12526813

Nakagawa, O., et al. (1999). HRT1, HRT2, and HRT3: a new subclass of bHLH transcription factors marking specific cardiac, somitic, and pharyngeal arch segments. Dev. Biol. 216(1): 72-84. PubMed Citation: 10588864

Nam, Y., et al. (2007). Cooperative assembly of higher-order Notch complexes functions as a switch to induce transcription. Proc. Natl. Acad. Sci. 104: 2103-2108. Medline abstract: 17284587

Nambu, P. A. and Nambu, J. R. (1996). The Drosophila fish-hook gene encodes a HMG domain protein essential for segmentation and CNS development. Development 122: 3467-75. PubMed Citation: 8951062

Neves, A. and Priess, J. R. (2005). The REF-1 family of bHLH transcription factors pattern C. elegans embryos through Notch-dependent and Notch-independent pathways. Dev. Cell 8(6): 867-79. 15935776

Ninkovic, J., et al. (2005).Inhibition of neurogenesis at the zebrafish midbrain-hindbrain boundary by the combined and dose-dependent activity of a new hairy/E(spl) gene pair. Development 132(1): 75-88.15590746

Niwa, Y., Masamizu, Y., Liu, T., Nakayama, R., Deng, C. X. and Kageyama, R. (2007). The initiation and propagation of Hes7 oscillation are cooperatively regulated by Fgf and notch signaling in the somite segmentation clock. Dev. Cell 13(2): 298-304. PubMed citation: 17681139

Niwa, Y., et al. (2011). Different types of oscillations in Notch and Fgf signaling regulate the spatiotemporal periodicity of somitogenesis. Genes Dev. 25(11): 1115-20. PubMed Citation: 21632822

Oates, A. C. and Ho, R. K. (2002). Hairy/E(spl)-related (Her) genes are central components of the segmentation oscillator and display redundancy with the Delta/Notch signaling pathway in the formation of anterior segmental boundaries in the zebrafish. Development 129: 2929-2946. 12050140

Ochoa-Espinosa, A., Yucel, G., Kaplan, L., Pare, A., Pura, N., Oberstein, A., Papatsenko, D. and Small S. (2005). The role of binding site cluster strength in Bicoid-dependent patterning in Drosophila. Proc. Natl. Acad. Sci. 102(14): 4960-5. 15793007

Ohsako, S., et al. (1994). Hairy function as a DNA-binding helix-loop-helix repressor of Drosophila sensory organ formation. Genes Dev. 8: 2743-55. PubMed Citation: 7958930

Ohtsuka, T., et al. (1999). Hes1 and Hes5 as Notch effectors in mammalian neuronal differentiation. EMBO J. 18(8): 2196-2207. PubMed Citation: 10205173

Ono, Y., Nakatani, T., Minaki, Y. and Kumai, M. (2010). The basic helix-loop-helix transcription factor Nato3 controls neurogenic activity in mesencephalic floor plate cells. Development 137(11): 1897-906. PubMed Citation: 20460368

Orenic, T. W., et al. (1993) The spatial organization of epidermal structures: hairy establishes the geometrical pattern of Drosophila leg bristles by delimiting the domains of achaete expression. Development 118: 9-20. PubMed Citation: 8375341

Palmeirim, I., et al. (1997). Avian hairy gene expression identifies a molecular clock linked to vertebrate segmentation and somitogenesis. Cell 91(5): 639-648. PubMed Citation: 9393857

Pasini, A., Jiang, Y.-J. and Wilkinson, D. G. (2004). Two zebrafish Notch-dependent hairy/Enhancer-of-split-related genes, her6 and her4, are required to maintain the coordination of cyclic gene expression in the presomitic mesoderm. Development 131: 1529-1541. 15023930

Payankaulam, S., and Arnosti, D. N. (2009). Groucho corepressor functions as a cofactor for the Knirps short-range transcriptional repressor. Proc. Natl. Acad. Sci. 106: 17314-17319. PubMed Citation: 19805071

Petrovic, J., Formosa-Jordan, P., Luna-Escalante, J. C., Abello, G., Ibanes, M., Neves, J. and Giraldez, F. (2014). Ligand-dependent Notch signaling strength orchestrates lateral induction and lateral inhibition in the developing inner ear. Development 141: 2313-2324. PubMed ID: 24821984

Pinto, M., and Lobe, C. G. (1996). Products of the grg (Groucho-related gene) family can dimerize through the amino-terminal Q domain. J. Biol. Chem. 271: 33026-31. PubMed Citation: 8955148

Poortinga, G., Watanabe, M. and Parkhurst, S. M. (1998). Drosophila CtBP: a Hairy-interacting protein required for embryonic segmentation and hairy-mediated transcriptional repression. EMBO J. 17(7): 2067-2078. PubMed Citation: 9524128

Qi, D., Bergman, M., Aihara, H., Nibu, Y., and Mannervik, M. (2008). Drosophila Ebi mediates Snail-dependent transcriptional repression through HDAC3-induced histone deacetylation. EMBO J. 27: 898-909. PubMed Citation: 18309295

Read, D., Levine, M. and Manley, J.L. (1992). Ectopic expression of the Drosophila tramtrack gene results in multiple embryonic defects, including repression of even skipped and fushi tarazu. Mech. Dev. 38(3): 183-95. PubMed Citation: 1457380

Rebeiz, M., et al. (2012). Ancestral and conserved cis-regulatory architectures in developmental control genes. Dev. Biol. 362: 282-294. PubMed Citation: 22185795

Rebeiz, M., Stone, T. and Posakony, J. W. (2005). An ancient transcriptional regulatory linkage. Dev. Biol. 281: 299-308. PubMed Citation: 1589398

Robin, C., et al. (2002). hairy: A quantitative trait locus for Drosophila sensory bristle number. Genetics 162: 155-164. 12242230

Rosenberg, M. I. and Parkhurst, S. M. (2002). Drosophila Sir2 is required for heterochromatic silencing and by euchromatic Hairy/E(Spl) bHLH repressors in segmentation and sex determination. Cell 109: 447-458. 12086602

Ross, J. M., Kalis, A. K., Murphy, M. W. and Zarkower, D. (2005). The DM domain protein MAB-3 promotes sex-specific neurogenesis in C. elegans by regulating bHLH proteins. Dev. Cell 8(6): 881-92. 15935777

Rossner, M. J., et al. (1998). SHARPs: mammalian enhancer-of-split- and hairy-related proteins coupled to neuronal stimulation. Mol. Cell. Neurosci. 10(3-4): 460-75. PubMed Citation: 9532582

Rushlow, C.A., et al. (1989). The Drosophila hairy protein acts in both segmentation and bristle patterning and shows homology to N-myc. EMBO J 8: 3095-3103. PubMed Citation: 2479541

Russell, S. R. H., et al. (1996). The Dichaete gene of Drosophila melanogaster encodes a SOX-domain protein required for embryonic segmentation. Development 122: 3669-76. PubMed Citation: 8951082

Sansom, S. N., et al. (2009). The level of the transcription factor Pax6 is essential for controlling the balance between neural stem cell self-renewal and neurogenesis. PLoS Genet. 5(6): e1000511. PubMed Citation: 19521500

Satow, T., et al. (2001). The basic helix-loop-helix gene hesr2 promotes gliogenesis in mouse retina. J. Neurosci. 21(4): 1265-1273. 11160397

Saulier-Le Dréan, B., et al. (1998). Dynamic changes in the functions of Odd-skipped during early Drosophila embryogenesis. Development 125: 4851-4861. PubMed Citation: 9806933

Schroeder, M. D., Greer, C. and Gaul, U. (2011). How to make stripes: deciphering the transition from non-periodic to periodic patterns in Drosophila segmentation. Development 138(14): 3067-78. PubMed Citation: 21693522

Sekiya, T. and Zaret, K. S. (2007). Repression by Groucho/TLE/Grg proteins: genomic site recruitment generates compacted chromatin in vitro and impairs activator binding in vivo. Mol. Cell 28: 291-303. PubMed Citation: 17964267

Shimizu, T., et al. (2010). Zinc finger genes Fezf1 and Fezf2 control neuronal differentiation by repressing Hes5 expression in the forebrain. Development 137(11): 1875-85. PubMed Citation: 20431123

Shimojo, H., Ohtsuka, T. and Kageyama, R. (2008). Oscillations in notch signaling regulate maintenance of neural progenitors. Neuron 58: 52-64. PubMed ID: 18400163

Shinga, J., et al. (2001). Early patterning of the prospective midbrain-hindbrain boundary by the HES-related gene XHR1 in Xenopus embryos. Mech. Dev. 109(2): 225-39. 11731236

Sieger, D., Tautz, D. and Gajewski, M. (2003). The role of Suppressor of Hairless in Notch mediated signalling during zebrafish somitogenesis. Mech. Dev. 120: 1083-1094. 14550536

Singh, N., Zhu, W. and Hanes, S. D. (2005). Sap18 is required for the maternal gene bicoid to direct anterior patterning in Drosophila melanogaster. Dev. Biol. 278: 242-254. PubMed Citation: 15649476

Solecki, D. J., et al. (2001). Activated Notch2 signaling inhibits differentiation of cerebellar granule neuron precursors by maintaining proliferation. Neuron 31: 557-568. 11545715

Soundararajan, H. C. and Bullock, S. L. (2014). The influence of dynein processivity control, MAPs, and microtubule ends on directional movement of a localising mRNA. Elife 3: e01596. PubMed ID: 24737859

Sugimori, M., et al. (2007). Combinatorial actions of patterning and HLH transcription factors in the spatiotemporal control of neurogenesis and gliogenesis in the developing spinal cord. Development 134(8): 1617-29. Medline abstract: 17344230

Taelman, V., et al. (2004). Sequences downstream of the bHLH domain of the Xenopus hairy-related transcription factor-1 act as an extended dimerization domain that contributes to the selection of the partners. Dev. Biol. 276(1): 47-63. 15531363

Tallafuß, A. and Bally-Cuif, L. (2003). Tracing of her5 progeny in zebrafish transgenics reveals the dynamics of midbrain-hindbrain neurogenesis and maintenance. Development 130: 4307-4323. 12900448

Tang, H., et al. (2008). Notch signaling maintains Leydig progenitor cells in the mouse testis. Development 135(22): 3745-53. PubMed Citation: 18927153

Tomita, K., et al. (1996). Mammalian hairy and Enhancer of split homolog 1 regulates differentiation of retinal neurons and is essential for eye morphogenesis. Neuron 16: 723-734. PubMed Citation: 8607991

Tomita, K., et al. (1999). The bHLH gene Hes1 is essential for expansion of early T cell precursors. Genes Dev. 13(9): 1203-10. PubMed Citation: 10323870

Tsai, C, and Gergen, J. P. (1994). Gap gene properties of the pair-rule gene runt during Drosophila segmentation. Development 120: 1671-1683. PubMed Citation: 8050373

Tsai, C. and Gergen. P. (1995). Pair-rule expression of the Drosophila fushi tarazu gene: a nuclear receptor response element mediates the opposing regulatory effects of runt and hairy. Development 121: 453-462. PubMed Citation: 7768186

Tulin, A., Stewart, D. and Spradling, A. C. (2002). The Drosophila heterochromatic gene encoding poly(ADP-ribose) polymerase (PARP) is required to modulate chromatin structure during development. Genes Dev. 16(16): 2108-19. 12183365

Tulin, A. and Spradling, A. (2003). Chromatin loosening by poly(ADP)-ribose polymerase (PARP) at Drosophila puff loci. Science 299: 560-562. 12543974

Umbhauer, M., Boucaut, J.-C. and Shi, D.-L. (2001). Repression of XMyoD expression and myogenesis by Xhairy-1 in Xenopus early embryo. Mech. Dev. 109: 61-68. 11677053

Ursuliak, Z., et al (1997). Differential accumulation of DPTP61F alternative transcripts: regulation of a protein tyrosine phosphatase by segmentation genes. Mech. Dev. 65(1-2): 19-30. PubMed Citation: 9256342

Van Doren, M., et al. (1994). Negative regulation of proneural gene activity: hairy is a direct transcriptional repressor of achaete. Genes Dev. 8: 2729-42. PubMed Citation: 7958929

Vasiliauskas, D. and Stern, C. D. (2000). Expression of mouse HES-6, a new member of the Hairy/Enhancer of split family of bHLH transcription factors. Mech. Dev. 98: 133-137. PubMed Citation: 11044617.

Vasiliauskas, D., Laufer, E. and Stern, C. D. (2003). A role for hairy1 in regulating chick limb bud growth. Dev. Biol. 262: 94-106. 14512021

Wang, L., Ding, L., Jones, C. A. and Jones, R. S. (2002). Drosophila Enhancer of zeste protein interacts with dSAP18. Gene 285: 119-125. PubMed Citation: 12039038

Wang, X., et al. (2007). Transcription elongation controls cell fate specification in the Drosophila embryo. Genes Dev. 21: 1031-1036. PubMed Citation: 17473169

Wesley, C. S. (1999). Notch and Wingless regulate expression of cuticle patterning genes. Mol. Cell. Biol. 19: 5743-5758. PubMed Citation: 10409762

Wrischnik, L. A. and Kenyon, C. J. (1997). The role of lin-22, a hairy/enhancer of split homolog, in patterning the peripheral nervous system of C. elegans. Development 124(15): 2875-2888. PubMed Citation: 9247331

Wu, L., et al. (2000). MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors. Nat Genet. 26(4): 484-9. 11101851

Yao, J., Lai, E. and Stifani, S. (2001). The winged-helix protein Brain Factor 1 interacts with Groucho and Hes proteins to repress transcription. Mol. Cell. Biol. 21: 1962-1972. 11238932

Yu, Y. and Pick, L. (1995). Non-periodic cues generate seven ftz stripes in the Drosophila embryo. Mech Dev 50: 163-175. PubMed Citation: 7619728

Zalc, A., Hayashi, S., Aurade, F., Brohl, D., Chang, T., Mademtzoglou, D., Mourikis, P., Yao, Z., Cao, Y., Birchmeier, C. and Relaix, F. (2014). Antagonistic regulation of p57kip2 by Hes/Hey downstream of Notch signaling and muscle regulatory factors regulates skeletal muscle growth arrest. Development 141: 2780-2790. PubMed ID: 25005473

Zhan, Y., et al. (2010). The bHLH transcription factor, hairy, refines the terminal cell fate in the Drosophila embryonic trachea. PLoS One 5(11): e14134. PubMed Citation: 21152432

Zhang, H. and Levine, M. (1999). Groucho and dCtBP mediate separate pathways of transcriptional repression in the Drosophila embryo. Proc. Natl. Acad. Sci. 96(2): 535-40. PubMed Citation: 9892668

Zeng, W., et al. (2000). naked cuticle encodes an inducible antagonist of Wnt signaling. Nature 403: 789-795. PubMed Citation: 10693810

Zheng, J. L., et al. (2000). Hes1 is a negative regulator of inner ear hair cell differentiation. Development 127: 4551-4560. PubMed Citation: 1023859

Zhu, W., Foehr, M., Jaynes, J. B., and Hanes, S. D. (2001). Drosophila SAP18, a member of the Sin3/Rpd3 histone deacetylase complex, interacts with Bicoid and inhibits its activity. Dev. Genes Evol. 211: 109-117. PubMed Citation: 11455422

date revised: 20 August 2014

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