extra macrochaetae
EMC has a high degree of homology to Inhibitor of Differentiation, otherwise known as ID protein. Like EMC, ID lacks the basic domain and is a negative regulator of MyoD (Ellis 1990 and Garrell 1990).
Transcription of a zebrafish Id homolog called Id6 is spatially regulated, and its pattern of transcription shows considerable
overlaps with those of other zebrafish genes with homology to Drosophila neurogenic
genes, such as Notch and Delta. Since all these genes are coexpressed in particular
cells, they may function together in a single genetic circuit in zebrafish as they do in
Drosophila. A zebrafish homolog of Drosophila AS-C proteins can activate
transcription of a CAT reporter gene by binding to an E-box in mouse 3T3 cells, either
alone or in conjunction with ZfE12. The activation of transcription is inhibited in the
presence of Id6. This indicates that the zebrafish gene described here is a genuine
member of the Id family, and suggests that it may serve a function similar to that of
the Drosophila gene extramachrochaete and mammalian Ids during development (Sawai, 1997).
The family of dominant-negative helix-loop-helix (dnHLH) transcriptional modulators consists of four mammalian
genes known to date: Id1, Id2, Id3 and Id4. Id3 exhibits a high abundance of transcripts at early stages that gradually declined at
most sites toward E15.5. Expression of Id3 in embryos was detected in brain, spinal cord, olfactory system,
branchial arches, limbs, sclerotome, endocardiac cushions, the outer lining of the gut, lung, retina, the collecting
system of the kidney, and in tooth anlagen. Although the abundance of mRNA decreased toward later stages in
most tissues, it remained high in teeth and kidney. This expression pattern suggests that Id3 functions both in
undifferentiated tissues and in organs which are in the process of differentiation. When compared to the
expression of other dnHLH genes, it becomes obvious that the pattern of Id3 mainly coincides with that of Id1.
This may reflect a partial redundancy in gene function. There is a mutually
exclusive expression of the proto-oncogene N-myc and Id3 (Ellmeier, 1995).
Three Emx genes have been characterized in a chondrichthyan, the dogfish Scyliorhinus canicula. Comparisons of these genes with their osteichthyan counterparts indicate that the gnathostome Emx genes belong to three distinct orthology classes, each containing one of the dogfish genes and either the tetrapod Emx1 genes (Emx1 class), the osteichthyan Emx2 genes (Emx2 class) or the zebrafish Emx1 gene (Emx3 class). While the three classes could be retrieved from the pufferfish genome data, no indication of an Emx3-related gene in tetrapods could be found in the databases, suggesting that this class may have been lost in this taxon. Expression pattern comparisons of the three dogfish Emx genes and their osteichthyan counterparts indicate that not only telencephalic, but also diencephalic Emx expression territories are highly conserved among gnathostomes. In particular, all gnathostomes share an early, dynamic phase of Emx expression, spanning presumptive dorsal diencephalic territories, which involves Emx3 in the dogfish, but another orthology class, Emx2, in tetrapods. In addition, the dogfish Emx2 gene shows a highly specific expression domain in the cephalic paraxial mesoderm from the end of gastrulation and throughout neurulation -- this suggests a role in the segmentation of the cephalic mesoderm (Derobert, 2002).
The formation of striated muscle in both vertebrates and invertebrates involves the activity of the
MyoD family of basic-helix-loop-helix (bHLH) transcription factors. The high degree of evolutionary
conservation of MyoD-related proteins, both in the sequence of their bHLH domains and in their
general developmental expression patterns, suggests that these factors are also conserved at the level
of function. This question was addressed directly using MyoD and E protein factors from vertebrates,
Drosophila, and Caenorhabditis elegans. Various MyoD and E factor combinations were tested for
their ability to interact in vitro and to function in vivo in the myogenic conversion of 10T1/2 mouse
fibroblasts. The ability of different homo- and heterodimers to bind DNA in vitro is an
accurate measure of biological activity in vivo. The inability of C. elegans CeE/DA or any other E protein to augment the activity of CeMyoD is consistent with the notion that CeMyoD functions as a homodomer rather than a heterdimer. A second assessment of conserved function comes
from the ability of these factors to rescue a C. elegans hlh-1 (CeMyoD) null mutation. Both Drosophila and chicken MyoD-related factors are able to rescue a C. elegans CeMyoD
loss-of-function mutation. These results demonstrate a remarkable degree of functional conservation of
these myogenic factors despite differences in E-protein interactions (Zhang, 1999).
Dimerization of three Id proteins (Id1, Id2, and Id3) with the four class A E proteins (E12, E47, E2-2, and HEB) and two
groups of class B proteins, the myogenic regulatory factors (MRFs: MyoD, myogenin, Myf-5 and MRF4/Myf-6), and the
hematopoietic factors (Scl/Tal-1, Tal-2, and Lyl-1) were tested in a quantitative yeast 2-hybrid assay. All three Ids bind with
high affinity to E proteins, but a much broader range of interactions is observed between Ids and the class B factors. Id1 and
Id2 interact strongly with MyoD (Drosophila homolog: Nautilus) and Myf-5 and weakly with myogenin and MRF4/Myf-6, whereas Id3 interacts weakly
with all four MRFs. Similar specificities are observed in co-immunoprecipitation and mammalian 2-hybrid analyses. No
interactions are found between the Ids and any of the hematopoietic factors. Each Id is able to disrupt the ability of E
protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. Mutagenesis
experiments show that the differences between Id1 and Id3 binding all map to three amino acids in the first helix and to a small
cluster of upstream residues. The Id proteins thus display a signature range of interactions with all of their potential dimerization
partners and may play a role in myogenesis which is distinct from that in hematopoiesis (Langlands, 1997).
The floating head (flh) gene in zebrafish encodes a homeodomain protein, which is essential for notochord formation along the entire body axis. flh orthologs, termed Not genes, have been isolated from chick and Xenopus, but no mammalian ortholog has yet been identified. Truncate (tc) is an autosomal recessive mutation in mouse that specifically disrupts the development of the caudal notochord. Truncate arose by a mutation in the mouse Not gene. The truncate allele (Nottc) contains a point mutation in the homeobox of Not that changes a conserved Phenylalanine residue in helix 1 to a Cysteine (F20C), and significantly destabilizes the homeodomain. Reversion of F20C in one allele of homozygous tc embryonic stem (ES) cells is sufficient to restore normal notochord formation in completely ES cell-derived embryos. A targeted mutation of Not was generated by replacing most of the Not coding sequence, including the homeobox with the eGFP gene. The phenotype of NoteGFP/eGFP, NoteGFP/tc, and Nottc/tc embryos is very similar but slightly more severe in NoteGFP/eGFP than in Nottc/tc embryos. This confirms allelism of truncate and Not, and indicates that tc is not a complete null allele. Not expression is abolished in Foxa2 and T mutant embryos, suggesting that Not acts downstream of both genes during notochord development. This is in contrast to zebrafish embryos, in which flh interacts with ntl (zebrafish T) in a regulatory loop and is essential for development of the entire notochord, and suggests that different genetic control circuits act in different vertebrate species during notochord formation (Abdelkhalek, 2004).
During development, the three major neural cell lineages, neurons, oligodendrocytes and astrocytes, differentiate in specific temporal orders at topologically defined positions. How the timing and position of their generation are coordinately regulated remains poorly understood. Evidence is presented that the transcription factors Pax6, Olig2 and Nkx2.2 (Nkx2-2), which define the positional identity of multipotent progenitors early in development, also play crucial roles in controlling the timing of neurogenesis and gliogenesis in the developing ventral spinal cord. Each of these factors has a unique ability to either enhance or inhibit the activities of the proneural helix-loop-helix (HLH) factors Ngn1 (Neurog1), Ngn2 (Neurog2), Ngn3 (Neurog3) and Mash1 (Ascl1), and the inhibitory HLH factors Id1 and Hes1, thereby regulating both the timing of differentiation of multipotent progenitors and their fate. Consistent with this, dynamic changes in their co-expression pattern in vivo are closely correlated to stage- and domain-specific generation of three neural cell lineages. Genetic manipulations of their temporal expression patterns in mice alter the timing of differentiation of neurons and glia. A molecular code model is proposed whereby the combinatorial actions of two classes of transcription factors coordinately regulate the domain-specific temporal sequence of neurogenesis and gliogenesis in the developing spinal cord (Sugimori, 2007).
This study demonstrates the combinatorial actions of two classes of transcription factors in the spatiotemporal control of neurogenesis and gliogenesis in the developing ventral spinal cord. In vitro data have shown that the proneural HLH factors Ngns and Mash1 intrinsically possess the activity to induce neurons and oligodendrocytes, respectively, whereas the inhibitory HLH factors Id1 and Hes1 stimulate astrogenesis. Yet, the timing of differentiation of neurons and glia in vivo is not determined a priori by the expression of these HLH factors. The data have shown that they do so in collaboration with Pax6, Olig2 and Nkx2.2, the primary function of which has been thought to be to specify the positional identity of progenitors (Sugimori, 2007).
These patterning factors participate in controlling both the timing of differentiation and cell fate by two mechanisms. First, they act to maintain progenitors undifferentiated by suppressing otherwise strong neurogenic and astrogenic activities of Ngns and Id1 and/or Hes1. The suppression of the neurogenic activity of Ngn2 by Olig2 is in accordance with the fact that the Olig2+ domain markedly expands while producing a large number of motoneurons. Such an activity, however, is not limited to Olig2, but common among three patterning factors. Second, three patterning factors differentially modulate the activity of Mash1. Mash1 itself promotes differentiation of both neurons and oligodendrocytes. Pax6, however, converts Mash1 to become selectively neurogenic, whereas Olig2 selectively enhances Mash1-dependent oligodendrogenesis. Thus, it is proposed that these two classes of transcription factors comprise a molecular code for the coordinated spatiotemporal control of neuro/gliogenesis. According to this model, the relative expression levels of patterning and HLH factors at the single cell level are crucial to determine the fate of multipotent progenitors. How the timing and expression level of individual factors are precisely controlled remains to be further investigated. How these two classes of transcription factors coordinately regulate genetic programs for differentiation of neurons and glia also needs to be examined in the future studies (Sugimori, 2007).
The expression of Id1, a helix-loop-helix protein that inhibits the activity of basic helix-loop-helix
transcription factors, is down-regulated during cellular differentiation and cell cycle withdrawal both in
tissue culture models and in mouse embryos. In order to study the mechanism of control of Idl
expression, a 210-bp enhancer element was isolated from the upstream region of the Id1 gene. Activity of this element recapitulates Id1 expression in C2C12 muscle cells and C3H10T1/2 fibroblasts: i.e., this
element is active in proliferating cells in the presence of serum and completely inactivated upon
mitogen depletion, cell cycle withdrawal, and (in the case of C2C12) induced myoblast differentiation.
Using linker-scanning mutations and site-directed mutagenesis in transient transfection experiments, two functional elements were identified within the 210-bp enhancer that are required for proper
serum responsiveness. One element (A) contains a consensus Egr-1 binding site and additional flanking
sequences required for optimal activity, and the other element (B) fits no known consensus. Gel shift
experiments demonstrate that the protein complex binding to the A site contains Egr-1 (Drosophila homolog: Stripe) and other
proteins. This complex as well as a protein complex that binds to the B site is lost within 24 h of serum
depletion, correlating with the down-regulation of Id1 expression. On the basis of these findings, it is
propose that the regulation of the Id1 response to serum is mediated in part by the early response gene
Egr-1 and as such provides a signaling link between the early-growth-response transcription factors
and dominant-negative helix-loop-helix proteins (Tournay, 1997).
Mammalian cDNAs encoding a rat (Rel-N1) and a human (Hel-N1) neuronal RNA-binding protein have
been cloned and characterized with respect to tissue specificity, neuroanatomical localization, and RNA
binding specificity. Both proteins are highly similar to the product of the Drosophila elav gene. However, in
situ hybridization of rat tissues demonstrate more restricted expression of Rel-N1 mRNA within a subset
of neurons of the hippocampus, cortex, and other regions of the gray matter, but not in glial cells or
white matter. In vitro RNA binding experiments demonstrate that Hel-N1 can bind to the 3' untranslated
region (3' UTR) of Id mRNA, a transcript that encodes a helix-loop-helix transcriptional repressor that is
abundantly expressed in undifferentiated neural precursors. Sequences characterized for Hel-N1 binding are also abundantly present in the 3' UTR of the Drosophila Extramacrochaetae mRNA, which encodes
an Id homolog. Thus, a potential link was identified between a neuronal 3' UTR RNA-binding protein
and regulatory transcription factors involved in neural development (King, 1994).
Id family helix-loop-helix (HLH) proteins are involved in the regulation of proliferation and differentiation for several cell
types. To identify cis- and trans-acting factors that regulate Id4 gene expression, the promoter regulatory
sequences of the human Id4 gene have been analyzed in transient transfections and gel mobility shift assays. Two functional
elements, both located downstream from the TATA motif, have been identified that control Id4 promoter activity. One element contains a
consensus E-box: the protein complex binding to the E-box contains the bHLH-zip upstream
stimulatory factor (USF) transcription factor. Enforced expression of USF1 leads to E-box-mediated stimulation of
promoter activity. The E-box also mediates stimulatory effects of several bHLH transcription factors, and co-expression of
Id4 blocks the stimulatory effect mediated by the bHLH factors. A second element is a GA motif, located downstream
from the transcriptional start sites. A 20-fold increase in transcriptional activity is seen as a result of the mutation of this GA motif. Gel-shift
analysis and transfections into Drosophila Schneider SL2 cells show that the repressor element is recognized by both
Sp1 and Sp3 factors. These data suggest that Id4 transcription control is highly complex, involving both negative and
positive regulatory elements, including a novel inhibitory function exerted by Sp1 and Sp3 transcription factors (Pagliuca, 1998).
In most postmitotic neurons, expression or activation of proteins that stimulate cell cycle progression or DNA replication results in
apoptosis. One potential exception to this generalization is neuroblastoma (NB), a tumor derived from the sympathoadrenal
lineage. NBs often express high levels of N-myc, a proto-oncogene that can potently activate key components of the cell cycle
machinery. In postmitotic sympathetic neurons, N-myc can induce S-phase entry while protecting neurons
from death caused by aberrant cell cycle reentry. Specifically, these experiments demonstrate that expression of N-myc at levels
similar to those in NBs causes sympathetic neurons to reenter S-phase, as monitored by 5-bromo-2-deoxyuridine incorporation and expression of cell cycle
regulatory proteins, and rescues them from apoptosis induced by withdrawal of their obligate survival factor, nerve growth factor. The N-myc-induced cell cycle
entry, but not enhanced survival, is inhibited by coexpression of a constitutively hypophosphorylated form of the retinoblastoma tumor suppressor protein,
suggesting that these two effects of N-myc are mediated by separate pathways. In contrast, N-myc does not cause S-phase entry in postmitotic cortical neurons. Thus,
N-myc both selectively causes sympathetic neurons to reenter the cell cycle and protects them from apoptosis, potentially contributing to their transformation to NBs. How does N-myc mediate this S-phase entry? The results demonstrating that coexpression of hypophosphorylated pRb rescues the BrdU incorporation argues that
N-myc mediates this effect via pRb. Such an effect could be mediated by direct interactions between N-myc and pRb, and it could also
be indirectly mediated via an N-myc-induced increase in levels of the inhibitory basic helix-loop-helix protein, Id2, which binds to hypophosphorylated pRb and
inhibits its ability to lock cells out of S-phase. An additional, potentially related mechanism involves N-myc-mediated downregulation of the cyclin-dependent kinase inhibitor p27, which in fibroblasts is essential for induction of cyclin E-cdk2 kinase activity, but not for S-phase entry. Although the data
presented here do not distinguish between these alternative explanations, it has been observed that p27 levels are decreased and Id2 levels increased in sympathetic
neurons overexpressing N-myc, suggesting that decreased p27 may collaborate with increased Id2 to trigger S-phase entry (Wartiovaara, 2002).
Bone morphogenetic protein (BMP) signaling inhibits the generation of
oligodendroglia and enhances generation of astrocytes by neural progenitor
cells both in vitro and in vivo. This study examined the mechanisms underlying
the effects of BMP signaling on glial lineage commitment. Treatment of
cultured neural progenitor cells with BMP4 induces expression of all four
members of the inhibitor of differentiation (ID) family of helix-loop-helix
transcriptional inhibitors and blocks oligodendrocyte (OL) lineage
commitment. Overexpression of Id4 or Id2 but not
Id1 or Id3 in cultured progenitor cells reproduces both the
inhibitory effects of BMP4 treatment on OL lineage commitment and the
stimulatory effects on astrogliogenesis. Conversely, decreasing the levels of
Id4 mRNA by RNA interference enhances OL differentiation and
inhibits the effects of BMP4 on glial lineage commitment. This suggests that
induction of Id4 expression mediates effects of BMP signaling.
Bacterial two-hybrid and co-immunoprecipitation studies demonstrate that ID4,
and to a lesser extent ID2, complexes with the basic-helix-loop-helix
transcription (bHLH) factors OLIG1 and OLIG2, which are required for the
generation of OLs. By contrast, ID1 and ID3 do not complex with the OLIG
proteins. In addition, the OLIG and ID proteins both interacted with the E2A
proteins E12 and E47. Further, exposure of cultured progenitor cells to BMP4
changes the intracellular localization of OLIG1 and OLIG2 from a predominantly
nuclear to a predominantly cytoplasmic localization. These observations
suggest that the induction of ID4 and ID2, and their sequestration of both
OLIG proteins and E2A proteins mediate the inhibitory effects of BMP signaling
on OL lineage commitment and contribute to the generation of astrocytes (Samanta, 2004).
Smad3, a transforming growth factor β/activin signaling effector, is expressed in discrete progenitor domains along the dorsoventral axis of the developing chick spinal cord. Restriction of Smad3 expression to the dP6-p2 and p3 domains together with exclusion from the motoneuron progenitor domain, are the result of the activity of key transcription factors responsible for patterning the neural tube. Smad3-mediated TGFβ activity promotes cell-cycle exit and neurogenesis by inhibiting the expression of Id proteins, and activating the expression of neurogenic factors and the cyclin-dependent-kinase-inhibitor p27kip1. Furthermore, Smad3 activity induces differentiation of selected neuronal subtypes at the expense of other subtypes. Within the intermediate and ventral domains, Smad3 promotes differentiation of ventral interneurons at the expense of motoneuron generation. Consequently, the absence of Smad3 expression from the motoneuron progenitor domain during pattern formation of the neural tube is a prerequisite for the correct generation of spinal motoneurons (Garcia-Campmany, 2007).
In a
search for novel factors that interact with Id1, a component of the 26 S proteasome, S5a, was identified that has previously
been implicated only in the recognition of ubiquitinated polypeptides destined for proteolysis. S5a interacts strongly with Id1,
less strongly with the basic helix-loop-helix proteins MyoD and E12, and not at all with other Id proteins. S5a restores DNA
binding by MyoD-Id1 and E12-Id1 heterodimers, enhances DNA binding by MyoD and E12 homodimers, and reverses
Id1-mediated repression of the muscle creatine kinase promoter during myogenic differentiation. Amino acids flanking the helix-loop-helix domain plus three residues in the first helix of Id1 impart S5a recognition.
This requires only the NH2-terminal half of S5a. S5a thus appears to promote the positive regulation of myogenic genes
through ubiquitin-independent mechanisms involving inhibition of Id1 and the enhancement of DNA binding by MyoD and
E12. This latter property may permit the selection of novel promoter binding sites during myogenesis (Anand, 1997).
In pre B cell leukemias containing the chromosome translocation t(1;19), Pbx1 (a homolog of Drosophila Extramachrochaetae) is converted
into a strong transactivator by fusion to the activation domain of the bHLH transcription factor E2A (a homolog of Drosophila Daugherless). The E2A-Pbx1 fusion protein
should therefore activate transcription of genes normally regulated by Pbx1. The subtractive process of representational
difference analysis was used to identify targets of E2A-Pbx1. E2A-Pbx1 can directly activate transcription of a novel member of
the fibroblast growth factor family of intercellular signaling molecules, FGF-15. FGF-15 is the most divergent in sequence from other known FGF family members. All FGF's share a conserved central region of approximately 120 amino acids which in FGF-1 and FGF-2 consists of 12 antiparallel beta strands that form a structure with threefold internal symmetry, called a beta-trefoil. Nine of these beta strands contain a highly conserved hydrophobic core residue. Eight of these hydrophobic residues are present in FGF-15. FGF-15 is between 15 and 30% identical to the other family members, with the greatest similarity to FGF-7 and FGF-1 and the least similarity to FGF-8. The FGF-15 gene is expressed in a regionally
restricted pattern in the developing nervous system, suggesting that FGF-15 may play an important role in regulating cell division and
patterning within specific regions of the embryonic brain, spinal cord and sensory organs (McWhirter, 1997).
Neural crest cells, a population of proliferative, migratory, tissue-invasive stem cells, are a defining feature of vertebrate embryos. These cells arise at the neural plate border during a time in development when precursors of the central nervous system and the epidermis are responding to the extracellular signals that will ultimately dictate their fates. Neural crest progenitors, by contrast, must be maintained in a multipotent state until after neural tube closure. Although the molecular mechanisms governing this process have yet to be fully elucidated, recent work has suggested that Myc functions to prevent premature cell fate decisions in neural crest forming regions of the early ectoderm. The small HLH protein Id3 is a Myc target that plays an essential role in the formation and maintenance of neural crest stem cells. A morpholino-mediated 'knockdown' of Id3 protein results in embryos that lack neural crest. Moreover, forced expression of Id3 maintains the expression of markers of the neural crest progenitor state beyond the time when they would normally be downregulated and blocks the differentiation of neural crest derivatives. These results shed new light on the mechanisms governing the formation and maintenance of a developmentally and clinically important cell population (Light, 2005).
Following their emigration from the neural tube, early migratory neural crest cells initially retain their stem cell-like characteristics, including the potential to contribute to the sensory neuronal, autonomic neuronal, glial, smooth muscle and ectomesenchymal lineages. However, these cells soon begin responding to signals that direct their development into specific neural crest derivatives, as evidenced by the downregulation of pan-neural crest markers expressed by the early progenitor population, and the expression of markers characteristic of specific differentiating lineages. Enforced misexpression of Id3 in the migratory neural crest population maintains the expression of markers characteristic of the progenitor state, and delays or prevents the differentiation of neural crest derivatives. For example, Id3-expressing cells sustain robust expression of Sox10, a factor that has itself been implicated in the maintenance of stem cell identity, and Slug, an important regulatory protein expressed by all neural crest precursor cells, long beyond the time that most neural crest cells on the control side of the embryo have downregulated these factors. Importantly, Id3 expression does not appear to irreversibly alter the potential of these cells. Once their pool of Id3 has turned over, neural crest cells are capable of responding to signals that direct the formation of specific derivatives such as melanocytes. These findings suggest a model in which Id family proteins expressed in the neural crest progenitor pool help control the timing with which these cells respond to differentiative signals during normal development. An alternative explanation of these findings, however, in which Id3 dictates the outcome of neural crest cell fate determination in a dose-dependant fashion, cannot br formally rule out. Future studies might profitably explore whether controlling the timing of release from Id3 activity can lead to excess recruitment of neural crest progenitors to fates other than melanocytes (Light, 2005).
Mechanisms that govern hematopoietic lineage specification, as opposed to the expansion of committed hematopoietic progenitors, from human pluripotent stem cells (hPSCs) have yet to be fully defined. This study show that within the family of genes called inhibitors of differentiation (ID), ID1 and ID3 negatively regulate the transition from lineage-specified hemogenic cells to committed hematopoietic progenitors during hematopoiesis of both human embryonic stem cells (hESCs) and human induced pluripotent stem cell (hiPSCs). Upon hematopoietic induction of hPSCs, levels of ID1 and ID3 transcripts rapidly increase, peaking at the stage of hemogenic precursor emergence, and then exclusively decrease during subsequent hematopoietic commitment. Suppression of ID1 and ID3 expression in hemogenic precursors using specific small interfering RNAs augments differentiation into committed hematopoietic progenitors, with dual suppression of ID1 and ID3 further increasing hematopoietic induction compared with upon knockdown of each gene alone. This inhibitory role of ID1 and ID3 directly affects hemogenic precursors and is not dependent on non-hemogenic cells of other lineages within developing human embryoid bodies from hESCs or hiPSCs. This study uniquely identifies ID1 and ID3 as negative regulators of the hPSC-hematopoietic transition from a hemogenic to a committed hematopoietic fate, and demonstrates that this is conserved between hESCs and hiPSCs (Hong, 2011).
Negative bHLH transcription factor Hes1 can inhibit neural stem cells (NSCs) from precocious neurogenesis through repressing proneural gene expression; therefore, sustenance of Hes1 expression is crucial for NSC pool maintenance. Ids, the dominant-negative regulators of proneural proteins, are expressed prior to proneural genes and share an overlapping expression pattern with Hes1 in the early neural tube of chick embryos. Overexpression of Id2 in the chick hindbrain upregulates Hes1 expression and inhibits proneural gene expression and neuronal differentiation. By contrast, Hes1 expression decreases, proneural gene expression expands, and neurogenesis occurs precociously in Id1;Id3 double knockout mice and in Id1-3 RNAi-electroporated chick embryos. Mechanistic studies show that Id proteins interact directly with Hes1 and release the negative feedback autoregulation of Hes1 without interfering with its ability to affect other target genes. These results indicate that Id proteins participate in NSC maintenance through sustaining Hes1 expression in early embryos (Bai, 2007).
ID genes are required for breast cancer colonization of the lungs, but the mechanism remains poorly understood. This study shows that Id1 expression induces a stem-like phenotype in breast cancer cells while retaining epithelial properties, contrary to the notion that cancer stem-like properties are inextricably linked to the mesenchymal state. During metastatic colonization, Id1 induces a mesenchymal-to-epithelial transition (MET), specifically in cells whose mesenchymal state is dependent on the Id1 target protein Twist1, but not at the primary site, where this state is controlled by the zinc finger protein Snail1. Knockdown of Id expression in metastasizing cells prevents MET and dramatically reduces lung colonization. Furthermore, Id1 is induced by transforming growth factor (TGF)-beta only in cells that have first undergone epithelial-to-mesenchymal transition (EMT), demonstrating that EMT is a prerequisite for subsequent Id1-induced MET during lung colonization. Collectively, these studies underscore the importance of Id-mediated phenotypic switching during distinct stages of breast cancer metastasis (Stankic, 2013).
Mechanistic studies of axon growth (see Drosophila axonogenesis)
during development are beneficial to the search for neuron-intrinsic
regulators of axon regeneration. This study discovered that in the
developing neuron from rat, Akt
signaling (see Drosophila Akt1
and insulin signaling) regulates
axon growth and growth cone formation through phosphorylation of serine 14
(S14) on Inhibitor of
DNA binding 2 (Id2) (see Drosophila emc).
This enhances Id2 protein stability by means of escape from proteasomal
degradation, and steers its localization to the growth cone, where Id2
interacts with radixin
(see Drosophila Moe) that
is critical for growth cone formation. Knockdown of Id2, or abrogation of
Id2 phosphorylation at S14, greatly impairs axon growth and the
architecture of growth cone. Intriguingly, reinstatement of Akt/Id2
signaling after injury in mouse hippocampal slices redeemed growth
promoting ability, leading to obvious axon regeneration. These results
suggest that Akt/Id2 signaling is a key module for growth cone formation
and axon growth, and its augmentation plays a potential role in CNS axonal
regeneration (Ko, 2016). Continued: Evolutionary Homologs part 2/2
Home page: The Interactive Fly © 1995, 1996 Thomas B. Brody, Ph.D.
The Interactive Fly resides on the
extra macrochaetae:
Biological Overview
| Regulation
| Developmental Biology
| Effects of Mutation
| References
Society for Developmental Biology's Web server.