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homeobrain: Biological Overview | References

The homeobox gene homeobrain (hbn) is located in the 57B region together with two other homeobox genes, Drosophila Retinal homeobox (DRx) and orthopedia (otp). All three genes encode transcription factors with important functions in brain development. hbn mutants are embryonic lethal and characterized by a reduction in the anterior protocerebrum, including the mushroom bodies, and a loss of the supraoesophageal brain commissure. This study conducted detailed expression analysis of hbn in later developmental stages. In the larval brain, hbn is expressed in all type II lineages and the optic lobes, including the medulla and lobula plug. The gene is expressed in the cortex of the medulla and the lobula rim in the adult brain. A new hbn^KOGal4 enhancer trap strain was generated by reintegrating Gal4 in the hbn locus through gene targeting, which reflects the complete hbn expression during development. Eight different enhancer-Gal4 strains covering 12 kb upstream of hbn, the two large introns and 5 kb downstream of the gene, were established and hbn expression was investigated. Several enhancers were characterized that drive expression in specific areas of the brain throughout development, from embryo to the adulthood. Finally, deletions of four of these enhancer regions were created through gene targeting, and their effects on the expression and function of hbn were analyzed. The complex expression of Hbn in the developing brain is regulated by several specific enhancers within the hbn locus. Each enhancer fragment drives hbn expression in several specific cell lineages, and with largely overlapping patterns, suggesting the presence of shadow enhancers and enhancer redundancy. Specific enhancer deletion strains generated by gene targeting display developmental defects in the brain. This analysis opens an avenue for a deeper analysis of hbn regulatory elements in the future (Hildebrandt, 2022).

NanoDam identifies novel temporal transcription factors conserved between the Drosophila central brain and visual system

Temporal patterning of neural progenitors is an evolutionarily conserved strategy for generating neuronal diversity. Type II neural stem cells in the Drosophila central brain produce transit-amplifying intermediate neural progenitors (INPs) that exhibit temporal patterning. However, the known temporal factors cannot account for the neuronal diversity in the adult brain. To search for new temporal factors, NanoDam, which enables rapid genome-wide profiling of endogenously-tagged proteins in vivo with a single genetic cross, was developed. Mapping the targets of known temporal transcription factors with NanoDam identified Homeobrain and Scarecrow (ARX and NKX2.1 orthologues) as novel temporal factors. Homeobrain and Scarecrow define middle-aged and late INP temporal windows and play a role in cellular longevity. Strikingly, Homeobrain and Scarecrow have conserved functions as temporal factors in the developing visual system. NanoDam enables rapid cell type-specific genome-wide profiling with temporal resolution and can be easily adapted for use in higher organisms (Tang, 2021).

The nervous system is generated by a relatively small number of neural stem cells (NSCs) and progenitors that are patterned both spatially and temporally. Spatial patterning confers differences between populations of NSCs, while changes in gene expression over time direct the birth order and subtype identity of neuronal progeny. Temporal transcription factor cascades determine neuronal birth order in the Drosophila embryonic central nervous system (CNS) and the larval central brain and optic lobe. In the central brain, Type II NSCs generate transit-amplifying intermediate neural progenitors (INPs), which divide asymmetrically to self-renew and generate daughter cells (ganglion mother cells or GMCs) in a manner analogous to human outer radial glial cells. GMCs in turn undergo a terminal cell division, generating neurons or glial cells that contribute to the adult central complex. The sequential divisions of INPs increase the quantity of neurons, which in turn creates a platform for generating wider neuronal diversity: eight Type II NSCs in each brain lobe give rise to at least 60 different neuronal subtypes. The tight control of progenitor temporal identity is crucial for the production of neuronal subtypes at the appropriate time and in the correct numbers. The INPs produced by the six dorsal-medial Type II lineages (DM1-6) sequentially express the temporal transcription factors Dichaete (D, a member of the Sox family), Grainy head (Grh, a Grh/CP2 family transcription factor) and Eyeless (Ey, a homologue of Pax6). These temporal factors were discovered initially by screening Type II lineages for restricted expression of neural transcription factors, using 60 different antisera. This non-exhaustive approach was able to find a fraction of the theoretically necessary temporal factors, leaving the true extent of temporal regulation and the identity of missing temporal factors open. Furthermore, the cross-regulatory interactions predicted in a temporal cascade, in which each temporal transcription factor activates expression of the next temporal factor and represses expression of the temporal factor preceding it, are not fulfilled solely by D, Grh and Ey (Tang, 2021).

Three further factors contribute to INP temporal progression, but they are expressed broadly rather than in discrete temporal windows: Osa, a SWI/SNF chromatin remodelling complex subunit, and two further transcription factors, Odd-paired (Opa) and Hamlet (Ham). Therefore, there must exist other transcription factors that are expressed in defined temporal windows and exhibit the regulatory interactions expected in a temporal cascade. It was postulated that other temporal factors, that contribute to generating the diversity of neuronal subtypes arising within each INP lineage, remain to be identified (Tang, 2021).

Given the feed-forward and feed-back transcriptional regulation previously observed in temporal transcription cascades, it was surmised that novel temporal factors would be amongst the transcriptional targets of D, Grh or Ey. Therefore, a novel approach, NanoDam, was devised to identify the genome-wide targets of transcription factors within their normal expression windows in vivo without cell isolation, cross linking or immunoprecipitation. Temporal factors are expressed transiently in a small pool of rapidly dividing progenitor cells. NanoDam provides a simple, streamlined approach to obtain genome-wide binding profiles in a cell-type-specific and temporally restricted manner (Tang, 2021).

Using NanoDam, the transcriptional targets of D, Grh and Ey were determined in INPs and, by performing single cell RNA sequencing, determined which of the directly bound loci were activated or repressed. Next, which of the target loci encoded transcription factors was assessed and whether these were expressed in restricted temporal windows within INPs. Where in the INP transcriptional cascade these factors acted was surveyed and whether they cross regulate the expression of other temporal transcription factor genes was ascertained, as expected for temporal factors. Finally, it was shown that the newly discovered temporal factors play the same roles, and exhibit the same cross regulatory interactions, in the temporal cascade in the developing visual system. This is particularly striking as theINPs and the NSCs of the developing optic lobe have different cells of origin and yet the mechanism they use to generate neural diversity is conserved (Tang, 2021).

Temporal patterning leads to the generation of neuronal diversity from a relatively small pool of neural stem or progenitor cells. Temporal regulation is achieved by the restricted expression of temporal transcription factors within precise developmental windows. The onset and duration of each temporal window in neural stem or progenitor cells must be regulated tightly in order for the appropriate subtypes of neurons to be generated at the correct time to establish functional neuronal circuits (Tang, 2021).

This study focused on the INPs of the Type II NSC lineages that generate the central complex of the Drosophila brain. Previously, INPs were shown to express sequentially the temporal factors D, Grh and Ey. Given the expectation that other temporal factors remained to be discovered, and that these were likely to be the transcriptional targets of the known temporal factors, a new technique called was used NanoDam to profile the binding targets of D, Grh and Ey with cell-type specificity and within their individual temporal windows (Tang, 2021).

NanoDam enables genome-wide profiling of any endogenously tagged chromatin-binding protein with a simple genetic cross, bypassing the need to generate Dam-fusion proteins, or the need for specific antisera or cell isolation. Furthermore, NanoDam profiles binding only in cells where the tagged protein is normally expressed. Binding within a subset of the protein's expression pattern can be achieved by controlling NanoDam with specific GAL4 drivers. To date, collaborative efforts have produced more than 3900 Drosophila lines expressing GFP-tagged proteins in their endogenous patterns. Approximately 93% of all transcription factors have been GFP-tagged in lines that are publicly available at stock centres. Lines that are not yet available can be rapidly generated by CRISPR/Cas9-mediated tagging (Tang, 2021).

NanoDam is thus a versatile tool that can be used as a higher throughput method to profile genome-wide binding sites of any chromatin associated protein. NanoDam can be readily adapted for use in other organisms to facilitate simpler and easier in vivoprofiling experiments, as hads been demonstrated previously for TaDa (Tang, 2021).

By combining the power of NanoDam with scRNA-seq, it was possible to identify scro and hbn as novel temporal factors in the INPs of Type II NSC lineages. It was shown that hbn and scro regulate the maintenance and transition of the middle-aged and late temporal windows. The mammalian homologues of ey (Pax6), hbn (Arx) and scro (Nkx2.1) are restricted to distinct progenitor populations in the developing mouse forebrain. This study found that scro regulates the late INP identity by repression of Ey. Interestingly, the loss of Nkx2.1 in the mouse forebrain leads to aberrant expression in ventral regions of the dorsal factor Pax6, suggesting that the repressive relationship between scro and ey may be conserved between Nkx2.1 and Pax6. Not all relationships appear to be conserved, however. It esd found that Hbn promotes progression through the middle-aged temporal stage and that maintenance of the middle-aged temporal window is regulated in part by interactions between Hbn and Grh. Arx mutant mice exhibit loss of upper layer (later-born) neurons but no change in the number of lower layer (early-born) neurons (Tang, 2021).

Intriguingly, the novel temporal factors identified in the INPs were also temporally expressed in optic lobe NSCs and the regulatory relationships between scro and Ey appeared to be conserved. This suggests that similar regulatory strategies may be shared between neural stem cells or progenitor cells inorder to regulate longevity and neuronal subtype production. The remarkable conservation of the regulatory interactions of scroin two different progenitor cell types with different origins in the Drosophila brain may also be translated to the context of mammalian neurogenesis, highlighting the possibility of a more generalised regulatory network used by stem and progenitor cells to regulate cell fate, progeny fate and proliferation (Tang, 2021).

The Type II lineages in Drosophila divide in a very similar manner to the outer radial glia (oRGs) that have been attributed to the rapid evolutionary expansion of the neocortex seen in humans and other mammals. Interestingly, oRGs show a shortened cell cycle length in primates in comparison to rodent progenitors, which increase cell cycle duration as development progresses . Investigating whether oRGs use temporally expressed factors to control longevity and cell cycle dynamics at different developmental stages in order to regulate neuronal subtype generation would be important for understanding neocortex development (Tang, 2021).

There is significant heterogeneity between the Type II lineages and this study has identified differences in the regulatory relationships of hbn and scro. For example, misexpression of Ey leads to an increase in scro in all lineages except DM 2 and 3, where scro expression is reduced. To date, Hbn is the only factor identified that activates Grh in DM1, the lineage that does not normally express Grh. The heterogeneity between lineages may be a consequence of variations in combinatorial binding of temporal factors, as the NanoDam data indicate. Although INPs share temporal factors, different DM lineages display subtle to striking differences when the temporal cascade is manipulated, demonstrating the likelihood that each DM employs unique temporal cascades. Combinatorial binding would enable more complex regulatory interactions that could refine or sub-divide temporal windows in the INPs (Tang, 2021).

The Drosophila homeodomain transcription factor Homeobrain is involved in the formation of the embryonic protocerebrum and the supraesophageal brain commissure

During the embryonic development of Drosophila melanogaster many transcriptional activators are involved in the formation of the embryonic brain. This study shows that the transcription factor Homeobrain (Hbn), a member of the 57B homeobox gene cluster, is an additional factor involved in the formation of the embryonic Drosophila brain. Using a Hbn antibody and specific cell type markers a detailed expression analysis during embryonic brain development was conducted. Hbn is expressed in several regions in the protocerebrum, including fibre tract founder cells closely associated with the supraesophageal brain commissure and also in the mushroom bodies. During the formation of the supraesophageal commissure, Hbn and FasII-positive founder cells build an interhemispheric bridge priming the commissure and thereby linking both brain hemispheres. The Hbn expression is restricted to neural but not glial cells in the embryonic brain. In a mutagenesis screen two mutant hbn alleles were generated that both show embryonic lethality. The phenotype of the hbn mutant alleles is characterized by a reduction of the protocerebrum, a loss of the supraesophageal commissure and mushroom body progenitors and also by a dislocation of the optic lobes. Extensive apoptosis correlates with the impaired formation of the embryonic protocerebrum and the supraesophageal commissure. These results show that Hbn is another important factor for embryonic brain development in Drosophila melanogaster (Kolb, 2021).

Drosophila Homeodomain-interacting protein kinase (Hipk) phosphorylates the homeodomain proteins Homeobrain, Empty spiracles, and Muscle segment homeobox.

The Drosophila homeodomain-interacting protein kinase (Hipk) is the fly representative of the well-conserved group of HIPKs in vertebrates. It was initially found through its characteristic interactions with homeodomain proteins. Hipk is involved in a variety of important developmental processes, such as the development of the eye or the nervous system. The present study set Hipk and the Drosophila homeodomain proteins Homeobrain (Hbn), Empty spiracles (Ems), and Muscle segment homeobox (Msh) in an enzyme-substrate relationship. These homeoproteins are transcription factors that function during Drosophila neurogenesis and are, at least in part, conserved in vertebrates. A physical interaction is revealed between Hipk and the three homeodomain proteins in vivo using bimolecular fluorescence complementation (BiFC). In the course of in vitro phosphorylation analysis and subsequent mutational analysis several Hipk phosphorylation sites of Hbn, Ems, and Msh were mapped. The phosphorylation of Hbn, Ems, and Msh may provide further insight into the function of Hipk during development of the Drosophila nervous system (Steinmetz, 2019).

Homeobrain, a novel paired-like homeobox gene is expressed in the Drosophila brain

The homeobrain (hbn) gene is a new paired-like homeobox gene that is expressed in the embryonic brain and the ventral nerve cord. Expression of homeobrain initiates during the blastoderm stage in the anterior dorsal head primordia and the gene is persistently expressed in these cells that form parts of the brain during later embryonic stages. An additional weaker expression pattern is detected in cells of the ventral nerve cord from stage 11 on. The homeodomain in the Homeobrain protein is most similar to the Drosophila proteins Rx, Aristaless and Munster. In addition, the localized brain expression patterns of homeobrain and Rx resemble each other. Two other homeobox genes, orthopedia and Rx are clustered in the 57B region along with homeobrain. The current evidence indicates that homeobrain, Rx and orthopedia form a homeobox gene cluster in which all the members are expressed in specific embryonic brain subregions (Walldorf, 2000).

Double abdomen in a short-germ insect: Zygotic control of axis formation revealed in the beetle Tribolium castaneum

The distinction of anterior versus posterior is a crucial first step in animal embryogenesis. In Drosophila, this axis is established by morphogenetic gradients contributed by the mother that regulate zygotic target genes. This principle has been considered to hold true for insects in general. This study investigated symmetry breaking in the beetle Tribolium castaneum, which among insects represents the more ancestral short-germ embryogenesis. Maternal Tc-germ cell-less is required for anterior localization of maternal Tc-axin, which represses Wnt signaling and promotes expression of anterior zygotic genes. Both RNAi targeting Tc-germ cell-less or double RNAi knocking down the zygotic genes Tc-homeobrain and Tc-zen1 led to the formation of a second growth zone at the anterior, which resulted in double-abdomen phenotypes. Conversely, interfering with two posterior factors, Tc-caudal and Wnt, caused double-anterior phenotypes. These findings reveal that maternal and zygotic mechanisms, including Wnt signaling, are required for establishing embryo polarity and induce the segmentation clock in a short-germ insect (Ansari, 2018).

Molecular regionalization in the compact brain of the meiofaunal annelid Dinophilus gyrociliatus (Dinophilidae)

Annelida is a morphologically diverse animal group that exhibits a remarkable variety in nervous system architecture (e.g., number and location of longitudinal cords, architecture of the brain). Despite this heterogeneity of neural arrangements, the molecular profiles related to central nervous system patterning seem to be conserved even between distantly related annelids. In particular, comparative molecular studies on brain and anterior neural region patterning genes have focused so far mainly on indirect-developing macrofaunal taxa. Therefore, analyses on microscopic, direct-developing annelids are important to attain a general picture of the evolutionary events underlying the vast diversity of annelid neuroanatomy. This study has analyzed the expression domains of 11 evolutionarily conserved genes involved in brain and anterior neural patterning in adult females of the direct-developing meiofaunal annelid Dinophilus gyrociliatus. The small, compact brain shows expression of dimmed, foxg, goosecoid, homeobrain, nk2.1, orthodenticle, orthopedia, pax6, six3/6 and synaptotagmin-1. Although most of the studied markers localize to specific brain areas, the genes six3/6 and synaptotagmin-1 are expressed in nearly all perikarya of the brain. All genes except for goosecoid, pax6 and nk2.2 overlap in the anterior brain region, while the respective expression domains are more separated in the posterior brain. These findings reveal that the expression patterns of the genes foxg, orthodenticle, orthopedia and six3/6 correlate with those described in Platynereis dumerilii larvae, and homeobrain, nk2.1, orthodenticle and synaptotagmin-1 resemble the pattern of late larvae of Capitella teleta. Although data on other annelids are limited, molecular similarities between adult Dinophilus and larval Platynereis and Capitella suggest an overall conservation of molecular mechanisms patterning the anterior neural regions, independent from developmental and ecological strategies, or of the size and configuration of the nervous system (Kerbl, 2016).

Cooperative Wnt-Nodal Signals Regulate the Patterning of Anterior Neuroectoderm

When early canonical Wnt is experimentally inhibited, sea urchin embryos embody the concept of a Default Model in vivo because most of the ectodermal cell fates are specified as anterior neuroectoderm. Using this model, this study describes how the combination of orthogonally functioning anteroposterior Wnt and dorsoventral Nodal signals and their targeting transcription factors, FoxQ2 and Homeobrain, regulates the precise patterning of normal neuroectoderm, of which serotonergic neurons are differentiated only at the dorsal/lateral edge. Loss-of-function experiments revealed that ventral Nodal is required for suppressing the serotonergic neural fate in the ventral side of the neuroectoderm through the maintenance of foxQ2 and the repression of homeobrain expression. In addition, non-canonical Wnt suppressed homeobrain in the anterior end of the neuroectoderm, where serotonergic neurons are not differentiated. Canonical Wnt, however, suppresses foxQ2 to promote neural differentiation. Therefore, the three-dimensionally complex patterning of the neuroectoderm is created by cooperative signals, which are essential for the formation of primary and secondary body axes during embryogenesis (Yaguchi, 2016).

A conserved cluster of three PRD-class homeobox genes (homeobrain, rx and orthopedia) in the Cnidaria and Protostomia

Homeobox genes are a superclass of transcription factors with diverse developmental regulatory functions, which are found in plants, fungi and animals. In animals, several Antennapedia (ANTP)-class homeobox genes reside in extremely ancient gene clusters (for example, the Hox, ParaHox, and NKL clusters) and the evolution of these clusters has been implicated in the morphological diversification of animal bodyplans. By contrast, similarly ancient gene clusters have not been reported among the other classes of homeobox genes (that is, the LIM, POU, PRD and SIX classes). Using a combination of in silico queries and phylogenetic analyses, this study found that a cluster of three PRD-class homeobox genes (Homeobrain (hbn), Rax (rx) and Orthopedia (otp)) is present in cnidarians, insects and mollusks (a partial cluster comprising hbn and rx is present in the placozoan Trichoplax adhaerens). This 'HRO' cluster is not present in deuterostomes; in fact, the Homeobrain gene appears to be missing from the chordate genomes that were examined, although it is present in hemichordates and echinoderms. To illuminate the ancestral organization and function of this ancient cluster, the constituent genes were mapped against the assembled genome of a model cnidarian, the sea anemone Nematostella vectensis, and characterized their spatiotemporal expression using in situ hybridization. In N. vectensis, these genes reside in a span of 33 kb with the same gene order as previously reported in insects. Comparisons of genomic sequences and expressed sequence tags revealed the presence of alternative transcripts of Nv-otp and two highly unusual protein-coding polymorphisms in the terminal helix of the Nv-rx homeodomain. A population genetic survey revealed the Rx polymorphisms to be widespread in natural populations. During larval development, all three genes are expressed in the ectoderm, in non-overlapping territories along the oral-aboral axis, with distinct temporal expression. In conclusion this study reports the first evidence for a PRD-class homeobox cluster that appears to have been conserved since the time of the cnidarian-bilaterian ancestor, and possibly even earlier, given the presence of a partial cluster in the placozoan Trichoplax. Very similar clusters comprising these three genes exist in Nematostella and diverse protostomes. Interestingly, in chordates, one member of the ancestral cluster (homeobrain) has apparently been lost, and there is no linkage between rx and orthopedia in any of the vertebrates. In Nematostella, the spatial expression of these three genes along the body column is not colinear with their physical order in the cluster but the temporal expression is, therefore, using the terminology that has been applied to the Hox cluster genes, the HRO cluster would appear to exhibit temporal but not spatial colinearity. It remains to be seen whether the mechanisms responsible for the evolutionary conservation of the HRO cluster are the same mechanisms responsible for cohesion of the Hox cluster and other ANTP-class homeobox clusters that have been widely conserved throughout animal evolution (Mazza, 2010).

The cnidarian-bilaterian ancestor possessed at least 56 homeoboxes: evidence from the starlet sea anemone

Homeodomain transcription factors are key components in the developmental toolkits of animals. While this gene superclass predates the evolutionary split between animals, plants, and fungi, many homeobox genes appear unique to animals. The origin of particular homeobox genes may, therefore, be associated with the evolution of particular animal traits. This study reports the first near-complete set of homeodomains from a basal (diploblastic) animal. Phylogenetic analyses were performed on 130 homeodomains from the sequenced genome of the sea anemone Nematostella vectensis along with 228 homeodomains from human and 97 homeodomains from Drosophila. The Nematostella homeodomains appear to be distributed among established homeodomain classes in the following fashion: 72 ANTP class; one HNF class; four LIM class; five POU class; 33 PRD class; five SINE class; and six TALE class. For four of the Nematostella homeodomains, there is disagreement between neighbor-joining and Bayesian trees regarding their class membership. A putative Nematostella CUT class gene is also identified. It is concluded that the homeodomain superclass underwent extensive radiations prior to the evolutionary split between Cnidaria and Bilateria. Fifty-six homeodomain families found in human and/or fruit fly are also found in Nematostella, though seventeen families shared by human and fly appear absent in Nematostella. Homeodomain loss is also apparent in the bilaterian taxa: eight homeodomain families shared by Drosophila and Nematostella appear absent from human (CG13424, EMXLX, HOMEOBRAIN, MSXLX, NK7, REPO, ROUGH, and UNC4), and six homeodomain families shared by human and Nematostella appear absent from fruit fly (ALX, DMBX, DUX, HNF, POU1, and VAX) (Ryan, 2006).

Capitella sp. I homeobrain-like, the first lophotrochozoan member of a novel paired-like homeobox gene family

The paired-like class of homeobox genes contains numerous distinct families, many of which have been implicated in a variety of developmental functions. This study reports the isolation and expression of a gene with high similarity to Drosophila melanogaster homeobrain from the polychaete annelid Capitella sp. I. The homeobrain-like (hbnl) gene is a paired-like gene that contains a conserved homeodomain, octapeptide region, alanine stretches, and an OAR domain. Gene orthology analyses of the homeodomain from CapI-hbnl places this gene in a new family of paired-like homeodomain genes that includes D. melanogaster homeobrain (hbn) and representatives from all major bilaterian clades as well as a cnidarian gene. CapI-hbnl expression is largely restricted to subsets of cells in the brain and eyes during larval development in Capitella sp. I. The earliest expression of CapI-hbnl is in small discrete cell clusters in the cerebral ganglia. This expression persists through late larval developmental stages whereas expression is absent in postmetamorphic juveniles. Outside the brain, expression is present on the ventral side of the larva in two small cell clusters, at the brain/pharyngeal border and in the anterior-most segment. CapI-hbnl shares features of brain expression with hbn, although in contrast to hbn, which is expressed along the length of the ventral nerve cord, CapI-hbnl has a restricted anterior expression pattern. CapI-hbnl represents an important neural marker for characterization of the annelid nervous system (Frobius, 2006).

Search PubMed for articles about Drosophila Homeodomain

Ansari, S., Troelenberg, N., Dao, V. A., Richter, T., Bucher, G. and Klingler, M. (2018). Double abdomen in a short-germ insect: Zygotic control of axis formation revealed in the beetle Tribolium castaneum. Proc Natl Acad Sci U S A 115(8): 1819-1824. PubMed ID: 29432152

Frobius, A. C. and Seaver, E. C. (2006). Capitella sp. I homeobrain-like, the first lophotrochozoan member of a novel paired-like homeobox gene family. Gene Expr Patterns 6(8): 985-991. PubMed ID: 16765105

Hildebrandt, K., Kolb, D., Kloppel, C., Kaspar, P., Wittling, F., Hartwig, O., Federspiel, J., Findji, I. and Walldorf, U. (2022). Regulatory modules mediating the complex neural expression patterns of the homeobrain gene during Drosophila brain development. Hereditas 159(1): 2. PubMed ID: 34983686

Kerbl, A., Martin-Duran, J. M., Worsaae, K. and Hejnol, A. (2016). Molecular regionalization in the compact brain of the meiofaunal annelid Dinophilus gyrociliatus (Dinophilidae). Evodevo 7(1): 20. PubMed ID: 27583125

Kolb, D., Kaspar, P., Kloppel, C. and Walldorf, U. (2021). The Drosophila homeodomain transcription factor Homeobrain is involved in the formation of the embryonic protocerebrum and the supraesophageal brain commissure. Cells Dev 165: 203657. PubMed ID: 33993980

Mazza, M. E., Pang, K., Reitzel, A. M., Martindale, M. Q. and Finnerty, J. R. (2010). A conserved cluster of three PRD-class homeobox genes (homeobrain, rx and orthopedia) in the Cnidaria and Protostomia. Evodevo 1(1): 3. PubMed ID: 20849646

Ryan, J. F., Burton, P. M., Mazza, M. E., Kwong, G. K., Mullikin, J. C. and Finnerty, J. R. (2006). The cnidarian-bilaterian ancestor possessed at least 56 homeoboxes: evidence from the starlet sea anemone, Nematostella vectensis. Genome Biol 7(7): R64. PubMed ID: 16867185

Steinmetz, E. L., Dewald, D. N., Luxem, N. and Walldorf, U. (2019). Drosophila Homeodomain-interacting protein kinase (Hipk) phosphorylates the homeodomain proteins Homeobrain, Empty spiracles, and Muscle segment homeobox. Int J Mol Sci 20(8). PubMed ID: 31010135

Tang, J. L. Y., Hakes, A. E., Krautz, R., Suzuki, T. Contreras, E. G., Fox, P. M. and Brand, A. H. (2021). NanoDam identifies novel temporal transcription factors conserved between the Drosophila central brain and visual system Biorxiv

Walldorf, U., Kiewe, A., Wickert, M., Ronshaugen, M. and McGinnis, W. (2000). Homeobrain, a novel paired-like homeobox gene is expressed in the Drosophila brain. Mech Dev. 96(1): 141-4. 10940637

Yaguchi, J., Takeda, N., Inaba, K. and Yaguchi, S. (2016). Cooperative Wnt-Nodal Signals Regulate the Patterning of Anterior Neuroectoderm. PLoS Genet 12(4): e1006001. PubMed ID: 27101101

date revised: 5 May 2022

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