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ABSTRACT: Dmrt genes encode a large family of transcription factors characterized by the presence of a DM domain, an unusual zinc finger DNA binding domain. While Dmrt genes are well known for their important role in sexual development in arthropodes, nematodes and vertebrates, several new findings indicate emerging functions of this gene family in other developmental processes. Here, we provide an overview of the evolution, structure and mechanisms of action of Dmrt genes. We summarize recent findings on their function in sexual regulation and discuss more extensively the role played by these proteins in somitogenesis and neural development.
Cellular and Molecular Life Sciences CMLS 03/2013; · 6.57 Impact Factor
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Damien Parlier,
Virginie Moers,
Claude Van Campenhout,
Julie Preillon,
Lucas Leclère,
Amandine Saulnier,
Maria Sirakov,
Henriette Busengdal,
Sadia Kricha,
Jean-Christophe Marine,
Fabian Rentzsch, Eric J Bellefroid
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ABSTRACT: The Dmrt (doublesex and mab-3 related transcription factor) genes encode a large family of evolutionarily conserved transcription factors whose function in sex specific differentiation has been well studied in all animal lineages. In vertebrates, their function is not restricted to the developing gonads. For example, Xenopus Dmrt4 is essential for neurogenesis in the olfactory system. Here we have isolated and characterized Xenopus Dmrt5 and found that it is coexpressed with Dmrt4 in the developing olfactory placodes. As Dmrt4, Dmrt5 is positively regulated in the ectoderm by neural inducers and negatively by proneural factors. Both Dmrt5 and Dmrt4 genes are also activated by the combined action of the transcription factor Otx2, broadly transcribed in the head ectoderm and of Notch signaling, activated in the anterior neural ridge. As for Dmrt4, knockdown of Dmrt5 impairs neurogenesis in the embryonic olfactory system and in neuralized animal caps. Conversely, its overexpression promotes neuronal differentiation in animal caps, a property that requires the conserved C-terminal DMA and DMB domains. We also found that the sea anenome Dmrt4/5 related gene NvDmrtb also induces neurogenesis in Xenopus animal caps and that conversely, its knockdown in Nematostella reduces elav-1 positive neurons. Together, our data identify Dmrt5 as a novel important regulator of neurogenesis whose function overlaps with that of Dmrt4 during Xenopus olfactory system development. They also suggest that Dmrt may have had a role in neurogenesis in the last common ancestor of cnidarians and bilaterians.
Developmental Biology 10/2012; · 4.07 Impact Factor
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Amandine Saulnier,
Marc Keruzore,
Sarah De Clercq,
Isabelle Bar,
Virginie Moers,
Dario Magnani,
Tessa Walcher,
Carol Filippis,
Sadia Kricha,
Damien Parlier,
Laurène Viviani,
Clinton K Matson,
Yasushi Nakagawa,
Thomas Theil,
Magdalena Götz,
Antonello Mallamaci,
Jean-Christophe Marine,
David Zarkower, Eric J Bellefroid
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ABSTRACT: Regional patterning of the cerebral cortex is initiated by morphogens secreted by patterning centers that establish graded expression of transcription factors within cortical progenitors. Here, we show that Dmrt5 is expressed in cortical progenitors in a high-caudomedial to low-rostrolateral gradient. In its absence, the cortex is strongly reduced and exhibits severe abnormalities, including agenesis of the hippocampus and choroid plexus and defects in commissural and thalamocortical tracts. Loss of Dmrt5 results in decreased Wnt and Bmp in one of the major telencephalic patterning centers, the dorsomedial telencephalon, and in a reduction of Cajal-Retzius cells. Expression of the dorsal midline signaling center-dependent transcription factors is downregulated, including Emx2, which promotes caudomedial fates, while the rostral determinant Pax6, which is inhibited by midline signals, is upregulated. Consistently, Dmrt5(-/-) brains exhibit patterning defects with a dramatic reduction of the caudomedial cortex. Dmrt5 is increased upon the activation of Wnt signaling and downregulated in Gli3(xt/xt) mutants. We conclude that Dmrt5 is a novel Wnt-dependent transcription factor required for early cortical development and that it may regulate initial cortical patterning by promoting dorsal midline signaling center formation and thereby helping to establish the graded expression of the other transcription regulators of cortical identity.
Cerebral Cortex 08/2012; · 6.54 Impact Factor
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ABSTRACT: The maternal-zygotic transition (MZT) is an embryonic event that overlaps with and plays key roles in primary germ layer specification in vertebrates. During MZT, maternally supplied mRNAs are degraded while zygotic transcripts are synthesized to either reinforce the already specified cell fate or to trigger new cell identity. Here, we show that forced expression of the RNA-binding protein, XSeb4R, in animal pole blastomeres of Xenopus embryos, inappropriately stabilizes transcripts there, including maternal Sox3. This leads to the impaired ability of the ectodermal progenitors to respond to factors regulating brain patterning and their eventual loss by apoptosis. XSeb4R protein binds specifically to the 3'UTR of Sox3 mRNA. XSeb4R gain-of-function in ectodermal explants reveals increased stability of the maternal Sox3 transcripts, associated with a robust Sox3 protein production. Conversely, whereas XSeb4R depletion abolishes VegT expression, the amount of the maternal Sox3 mRNA is rather increased but without augmentation in the amount of Sox3 protein. Moreover, XSeb4R protein knockdown leads to the modification of the ectoderm-mesoderm boundary, marked by expanded/shifted expression of the mesodermal marker genes such as Xbra and Apod, followed by an expression inhibition of Epi. K., an ectodermal marker. Overall, our data suggest XSeb4R as a novel player in gene expression regulation, acting at the posttranscriptional level during ectoderm specification in Xenopus.
Developmental Biology 03/2012; 363(2):362-72. · 4.07 Impact Factor
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ABSTRACT: The Homez gene encodes a protein with three atypical homeodomains and two leucine zipper motifs of unknown function. Here we show that during neurula stages, Xenopus Homez is broadly expressed throughout the neural plate, the strongest expression being detected in the domains where primary neurons arise. At later stages, Homez is maintained throughout the central nervous system in differentiating progenitors. In accordance with this expression, Homez is positively regulated by neural inducers and by Ngnr1 and negatively by Notch signaling. Interference with Homez function in embryos by injection of an antisense morpholino oligonucleotide results in the specific disruption of the expression of late neuronal markers, without affecting the expression of earlier neuronal and early neurectodermal markers. Consistent with this finding, Homez inhibition also interferes with the expression of late neuronal markers in Ngnr1 overexpressing animal cap explants and in Notch inhibited embryos. In gain of function experiments, Homez inhibits the expression of late neuronal markers but has no effect on earlier ones. These data suggest a role for Homez in neuronal development downstream of proneural/neurogenic genes.
Biochemical and Biophysical Research Communications 11/2011; 415(1):11-6. · 2.48 Impact Factor
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ABSTRACT: A complex set of extracellular signals is required for neural crest (NC) specification. However, how these signals function to coordinate cell-cycle progression and differentiation remains poorly understood. Here, we report in Xenopus a role for the transcription factor signal transducers and activators of transcription-3 (Stat3) in this process downstream of FGF signalling. Depletion of Stat3 inhibits NC gene expression and cell proliferation, whereas overexpression expands the NC domain and promotes cell proliferation. Stat3 is phosphorylated and activated in ectodermal cells by FGFs through binding with FGFR4. Stat3 activation is also modulated by Hairy2 and Id3 proteins that, respectively, facilitate and disrupt Stat3-FGFR4 complex formation. Furthermore, distinct levels of Stat3 activity control Hairy2 and Id3 transcription, leading to Stat3 self-regulation. Finally, high Stat3 activity maintains cells in an undifferentiated state, whereas low activity promotes cell proliferation and NC differentiation. Together, our data suggest that Stat3, downstream of FGFs and under the positive and negative feedback regulation of Hairy2 and Id3, plays an essential role in the coordination of cell-cycle progression and differentiation during NC specification.
The EMBO Journal 10/2009; 29(1):55-67. · 9.20 Impact Factor
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ABSTRACT: BBP proteins constitute a subclass of CUL3 interacting BTB proteins whose in vivo function remains unknown. Here, we show that the Xenopus BBP gene BTBD6 and the single Drosophila homologue of mammalian BBP genes lute are strongly expressed in the developing nervous system. In Xenopus, BTBD6 expression responds positively to proneural and negatively to neurogenic gene overexpression. Knockdown of BTBD6 in Xenopus or loss of Drosophila lute result in embryos with strong defects in late neuronal markers and strongly reduced and disorganized axons while early neural development is unaffected. XBTBD6 knockdown in Xenopus also affects muscle development. Together, these data indicate that BTBD6/lute is required for proper embryogenesis and plays an essential evolutionary conserved role during neuronal development.
Developmental Dynamics 11/2008; 237(11):3352-60. · 2.54 Impact Factor
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ABSTRACT: Loss of function studies have shown that the Xenopus helix-loop-helix transcription factor Hairy2 is essential for neural crest formation and maintains cells in a mitotic undifferentiated state. However, its position in the genetic cascade regulating neural crest formation and its relationship with other neural crest regulators remain largely unknown. Here we find that Hairy2 is regulated by BMP, FGF and Wnt and that it is only required downstream of BMP and FGF for neural crest formation. We show that Hairy2 overexpression represses neural crest and upregulates neural border genes at early stages while it expands a subset of them in later embryos. We show that Hairy2 downregulates Id3, another essential HLH neural crest regulator, through attenuation of BMP signaling. Knockdown and rescue experiments indicate that Id3 protein, which physically interacts with Hairy2, negatively regulates Hairy2 activity. However, Id3 is required to allow Hairy2 to promote neural crest formation. Together, our results provide evidence that Hairy2 acts downstream of FGF and BMP signals at the neural border to maintain cells in an undifferentiated state, and that Hairy2-Id3 interactions play an essential role in neural crest progenitor specification.
Developmental Biology 09/2008; 322(2):355-67. · 4.07 Impact Factor
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ABSTRACT: The Xenopus helix-loop-helix transcription factor Hairy2 is essential for neural crest progenitor survival and maintains cells in a mitotic undifferentiated pre-neural crest state. However, its mode of action remains largely unknown. Here we show that a Hairy2 DNA-binding mutant is unable to promote cell survival and to upregulate the expression of early neural border genes but is capable to increase cell proliferation and to expand NC in late embryos. We found that Hairy2 transiently activates in a DNA-binding independent manner the expression of the Notch ligand Delta1 and that Delta1 is required for Hairy2 to promote cell proliferation and to expand NC. Finally, we provide evidence that Hairy2 induces Delta1 through the transcription factor Stat3. Together, these results suggest that Hairy2 has a dual mode of action and may function at the neural plate border through both a DNA-binding and a non-DNA-binding Stat3-Delta1 mediated mechanism.
Developmental Biology 08/2008; 322(2):368-80. · 4.07 Impact Factor
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ABSTRACT: The evolutionarily conserved IA1 (Insm1) gene is strongly expressed in the developing nervous system. Here, we show that IA1 is expressed during Xenopus laevis embryogenesis in neural plate primary neurons as well as in a population of uncharacterized anteroventral cells that form in front of the cement gland and that we identified as noradrenergic neurons. We also show that the formation of those anteroventral cells is dependent on BMPs and inhibited by Notch and that it is regulated by the transcription factors Xash1, Phox2, and Hand2. Finally, we provide functional evidence suggesting that IA1 may also play a role in their formation. Together, our results reveal that IA1 constitutes a novel player downstream of Xash1 in the formation of a previously unidentified population of Xenopus noradrenergic primary neurons.
Developmental Dynamics 08/2008; 237(8):2147-57. · 2.54 Impact Factor
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ABSTRACT: Wnt signaling pathways are essential for embryonic patterning, and they are disturbed in a wide spectrum of diseases, including cancer. An unresolved question is how the different Wnt pathways are supported and regulated. We previously established that the postsynaptic density 95/disc-large/zona occludens (PDZ) protein syntenin binds to syndecans, Wnt coreceptors, and known stimulators of protein kinase C (PKC)alpha and CDC42 activity. Here, we show that syntenin also interacts with the C-terminal PDZ binding motif of several Frizzled Wnt receptors, without compromising the recruitment of Dishevelled, a key downstream Wnt-signaling component. Syntenin is coexpressed with cognate Frizzled during early development in Xenopus. Overexpression and down-regulation of syntenin disrupt convergent extension movements, supporting a role for syntenin in noncanonical Wnt signaling. Syntenin stimulates c-jun phosphorylation and modulates Frizzled 7 signaling, in particular the PKCalpha/CDC42 noncanonical Wnt signaling cascade. The syntenin-Frizzled 7 binding mode indicates syntenin can accommodate Frizzled 7-syndecan complexes. We propose that syntenin is a novel component of the Wnt signal transduction cascade and that it might function as a direct intracellular link between Frizzled and syndecans.
Molecular biology of the cell 05/2008; 19(4):1594-604. · 5.98 Impact Factor
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Leo A van Grunsven,
Vincent Taelman,
Christine Michiels,
Griet Verstappen,
Jacob Souopgui,
Massimo Nichane,
Emmanuelle Moens,
Karin Opdecamp,
Jessica Vanhomwegen,
Sadia Kricha,
Danny Huylebroeck, Eric J Bellefroid
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ABSTRACT: The DNA-binding transcription factor Smad-interacting protein-1 (Sip1) (also named Zfhx1b/ZEB2) plays essential roles in vertebrate embryogenesis. In Xenopus, XSip1 is essential at the gastrula stage for neural tissue formation, but the precise molecular mechanisms that underlie this process have not been fully identified yet. Here we show that XSip1 functions as a transcriptional repressor during neural induction. We observed that constitutive activation of BMP signaling prevents neural induction by XSip1 but not the inhibition of several epidermal genes. We provide evidence that XSip1 binds directly to the BMP4 proximal promoter and modulates its activity. Finally, by deletion and mutational analysis, we show that XSip1 possesses multiple repression domains and that CtBPs contribute to its repression activity. Consistent with this, interference with XCtBP function reduced XSip1 neuralizing activity. These results suggest that Sip1 acts in neural tissue formation through direct repression of BMP4 but that BMP-independent mechanisms are involved as well. Our data also provide the first demonstration of the importance of CtBP binding in Sip1 transcriptional activity in vivo.
Developmental Biology 07/2007; 306(1):34-49. · 4.07 Impact Factor
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ABSTRACT: The mechanisms by which a subset of mesodermal cells are committed to a nephrogenic fate are largely unknown. In this study, we have investigated the role of retinoic acid (RA) signalling in this process using Xenopus laevis as a model system and Raldh2 knockout mice. Pronephros formation in Xenopus embryo is severely impaired when RA signalling is inhibited either through expression of a dominant-negative RA receptor, or by expressing the RA-catabolizing enzyme XCyp26 or through treatment with chemical inhibitors. Conversely, ectopic RA signalling expands the size of the pronephros. Using a transplantation assay that inhibits RA signalling specifically in pronephric precursors, we demonstrate that this signalling is required within this cell population. Timed antagonist treatments show that RA signalling is required during gastrulation for expression of Xlim-1 and XPax-8 in pronephric precursors. Moreover, experiments conducted with a protein synthesis inhibitor indicate that RA may directly regulate Xlim-1. Raldh2 knockout mouse embryos fail to initiate the expression of early kidney-specific genes, suggesting that implication of RA signalling in the early steps of kidney formation is evolutionary conserved in vertebrates.
Developmental Biology 12/2006; 299(1):35-51. · 4.07 Impact Factor
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ABSTRACT: Neurons and glial cells differentiate from common multipotent precursors in the vertebrate retina. We have identified a novel member of the hairy/Enhancer of split [E(spl)] gene family in Xenopus, XHes2, as a regulator to bias retinal precursor cells towards a glial fate. XHes2 expression is predominantly restricted to sensory organ territories, including the retina. Using in vivo lipofection in the optic vesicle, we found that XHes2 overexpression dramatically increases gliogenesis at the expense of neurogenesis. This increase in glial cells correlates with a delayed cell cycle withdrawal of some retinal progenitors. In addition, birthdating experiments suggest that XHes2 deviates some early born cell types towards a glial fate that would normally have given rise to neurons. Conversely, a significant inhibition of glial differentiation is observed upon XHes2 loss of function. The gliogenic activity of XHes2 relies on its ability to inhibit neuronal differentiation by at least two distinct mechanisms: it not only negatively regulates XNgnr1 and NeuroD transcription, but it also physically interacts with a subset of proneural bHLH proteins.
Development 11/2006; 133(20):4097-108. · 6.60 Impact Factor
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ABSTRACT: The embryonic pronephric kidneys of Xenopus and zebrafish serve as models to study vertebrate nephrogenesis. Recently, multiple subdomains within the Xenopus pronephros have been defined based on the expression of several transport proteins. In contrast, very few studies on the expression of renal transporters have been conducted in zebrafish. We have recently shown that the anterior and posterior segments of the zebrafish pronephric duct may correspond to the proximal tubule and distal tubule/duct compartments of the Xenopus and higher vertebrate pronephros, respectively. Here, we report the embryonic expression pattern of the Na(+)/PO(4) cotransporter SLC20A1 (PiT1/Glvr-1) gene encoding a type III sodium-dependent phosphate cotransporter in Xenopus and zebrafish. In Xenopus, SLC20A1 mRNA is expressed in the somitic mesoderm and lower level of expression is detected in the neural tube, eye, and neural crest cells. From stage 25, SLC20A1 is also detectable in the developing pronephros where expression is restricted to the late portion of the distal pronephric tubules. In zebrafish, SLC20A1 is transcribed from mid-somitogenesis in the anterior part of the pronephros where its expression corresponds to the rostral portion of the expression of other proximal tubule-specific markers. Outside the pronephros, lower level of SLC20A1 expression is also observed in the posterior cardinal and caudal veins. Based on the SLC20A1 expression domain and that of other transporters, four segments have been defined within the zebrafish pronephros. Together, our data reveal that the zebrafish and Xenopus pronephros have non-identical proximo-distal organizations.
Gene Expression Patterns 11/2006; 6(7):667-72. · 2.02 Impact Factor
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ABSTRACT: Notch signaling has been shown to play a role in cell fate decisions in the Xenopus pronephros anlagen. Here, we show that the Xenopus Hairy-related transcription factor (HRT) gene XHRT1, and the Hairy/Enhancer of split (HES) genes Xhairy1, Xhairy2b, esr9 and esr10, have distinct restricted dynamic expression patterns during pronephros development, and that their expression is regulated by Notch. XHRT1, which is the earliest and strongest gene expressed in the pronephric region, is initially transcribed predominantly in the forming glomus, where it is downregulated by antisense morpholino oligonucleotide inhibition of xWT1. Later, it is activated in the most dorsoanterior part of the pronephros anlagen that gives rise to the proximal tubules. In agreement with this dynamic expression profile, we found that early activation of Notch favors glomus, whereas only later activation promotes proximal tubule formation. We show that, among the bHLH-O factors tested, only XHRT1 efficiently inhibits distal tubule and duct formation, and that only its translational inhibition causes a reduction of the expression of proximal tubule and glomus markers. Using domain swap experiments, we found that the XHRT1 C-terminal region is crucial for its activity. Together, our results provide evidence that XHRT1 plays an important role in glomerular development and early proximodistal patterning that is distinct from those of the other pronephric bHLH repressors.
Development 09/2006; 133(15):2961-71. · 6.60 Impact Factor
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ABSTRACT: The ecotropic viral integration site 1 (Evi1) and related MEL1 (MDS1/Evi1-like gene 1) genes are zinc finger oncogenic transcription factors involved in myeloid leukaemia. Here, we show that in Xenopus, Evi1 and MEL1 have partially overlapping restricted embryonic expression profiles. Within the pronephros, Evi1 and MEL1 are sequentially expressed within the distal tubule and duct compartments, Evi1 transcription being detected prior to any sign of pronephric morphogenesis. In the pronephros of zebrafish embryos, Evi1 expression is restricted to the posterior portion of the duct, the anterior portion having characteristics of proximal tubules. In the Xenopus pronephros, Evi1 expression is upregulated by retinoid signaling and repressed by overexpression of xWT1 and by Notch signaling. Overexpression of Evi1 from late neurula stage specifically inhibits the expression of proximal tubule and glomus pronephric markers. We show that the first zinc finger and CtBP interaction domains are required for this activity. Overexpression of a hormone-inducible Evi1-VP16 antimorphic fusion with activation at neurula stage disrupts distal tubule and duct formation and expands the expression of glomus markers. Although overexpression of this construct also causes in many embryos a reduction of proximal tubule markers, embryos with expanded and ectopic staining have been also observed. Together, these data indicate that Evi1 plays a role in the proximo-distal patterning of the pronephros and suggest that it may do so by functioning as a CtBP dependent repressor.
Developmental Biology 07/2006; 294(1):203-19. · 4.07 Impact Factor
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ABSTRACT: The zinc finger/homeo-domain transcription factor (zfh x 1) family in vertebrates consists of two members, deltaEF1 and SIP1. They have been proposed to display antagonistic activities in the interpretation of Smad-dependent TGFbeta signaling during mesoderm formation. We cloned Xenopus deltaEF1 cDNA, analyzed the expression profile of the gene, and compared the inducing and interacting properties of the protein to that of XSIP1. Whereas XSIP1 RNA is selectively expressed in the early developing nervous system, we show that XdeltaEF1 gene transcription is only activated during neurulation and that its expression is restricted to the paraxial mesoderm. From early tail bud stage, XdeltaEF1 and XSIP1 are coexpressed in migratory cranial neural crest, in the retina, and in the neural tube. Overproduction of XdeltaEF1 in RNA-injected embryos, like that of XSIP1, reduced the expression of BMP-dependent genes but only XSIP1 has the ability to induce neural markers. We find that XdeltaEF1 and XSIP1 can both form complexes, although with different efficiency, with Smad3, with the coactivators p300 and pCAF, and with the corepressor CtBP1. Together, these results indicate that deltaEF1 and SIP1 do not function as antagonists during Xenopus early embryogenesis but do display different repression efficiencies and interaction properties.
Developmental Dynamics 07/2006; 235(6):1491-500. · 2.54 Impact Factor
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ABSTRACT: XHRT1 is a member of the HRT/Hey protein subfamily that are known as Notch effectors. XHRT1 is expressed in the developing floor plate and encodes a basic helix-loop-helix (bHLH) transcription repressor. Here, we show that XHRT1 misexpression in the neural plate inhibits differentiation of neural precursor cells and thus may be important for floor plate cells to prevent them from adopting a neuronal fate. Deletion analysis indicated that inhibition of differentiation by XHRT1 requires the DNA-binding bHLH motif and either the Orange domain or the C-terminal region. XHRT1 could efficiently homodimerize and heterodimerize with hairy proteins. Among those hairy genes, Xhairy2b shows extensive overlap of expression with XHRT1 in floor plate precursors and may be a biologically relevant XHRT1 partner. Dimerization is mediated through both the bHLH and downstream sequences, the Orange domain being particularly important for the efficiency of the interaction. Using chimeric constructs between XHRT1 and the ESR9 bHLH-O protein that does not interact with Xhairy1 and Xhairy2b, we found that both the bHLH domain and downstream sequences of XHRT1 were required for heterodimerization with Xhairy2b, while only the XHRT1 sequences downstream of the Orange domain are required for the interaction with Xhairy1. Together, these results suggest that XHRT1 plays a role in floor plate cell development and highlight the importance of the Orange and downstream sequences in dimerization and in the selection of the bHLH partners.
Developmental Biology 01/2005; 276(1):47-63. · 4.07 Impact Factor
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ABSTRACT: Hairy-related transcription factors (HRTs) constitute a recently identified subfamily of basic-helix-loop-helix transcription factors containing an Orange domain (bHLH-O factors). As compared to the related HES proteins, HRTs exhibit distinct DNA-binding activities in vitro and the molecular mechanisms underlying their transcriptional activity remain poorly understood. We have identified here the sequence "ggCACGTGcc" as predominant binding site for Xenopus HRT1 (XHRT1). In transiently transfected 3T3 cells, XHRT1 represses the expression of a luciferase reporter gene under the control of multimerized XHRT1 binding sites. Deletion analysis indicated that repression by XHRT1 requires the presence of the DNA-binding bHLH motif and the Orange domain. However, the presence of the sequence motif YRPWGTEIGAF located at the very C-terminus of XHRT1 is dispensable. Accordingly, the groucho co-repressor, which is known to mediate transcriptional repression by HES factors through binding their C-terminal WRPW sequence, does not recognize the related YRPW motif present in the C-terminal part of XHRT1 significantly in vitro. As the C-terminus of HRTs is well conserved, our observation indicates that this part of HRTs, unlike the corresponding part of HES proteins, does not recruit the groucho co-repressor efficiently.
Biochimica et Biophysica Acta 11/2004; 1680(1):46-52. · 4.66 Impact Factor
