title: Induction and dorsal restriction of Paired-box 3 (Pax3) gene expression in the caudal neuroectoderm is mediated by integration of multiple pathways on a short neural crest enhancer.
abstract: Pax3 encodes a paired-box transcription factor with key roles in neural crest and neural tube ontogenesis. Robust control of Pax3 neural expression is ensured by two redundant sets of cis-regulatory modules (CRMs) that integrate anterior-posterior (such as Wnt-βCatenin signaling) as well as dorsal-ventral (such as Shh-Gli signaling) instructive cues. In previous work, we sought to characterize the Wnt-mediated regulation of Pax3 expression and identified the Cdx transcription factors (Cdx1/2/4) as critical intermediates in this process. We identified the neural crest enhancer-2 (NCE2) from the 5'-flanking region of Pax3 as a Cdx-dependent CRM that recapitulates the restricted expression of Pax3 in the mouse caudal neuroectoderm. While this is consistent with a key role in relaying the inductive signal from posteriorizing Wnt ligands, the broad expression of Cdx proteins in the tailbud region is not consistent with the restricted activity of NCE2. This implies that other positive and/or negative inputs are required and, here, we report a novel role for the transcription factor Zic2 in this regulation. Our data strongly suggests that Zic2 is involved in the induction (as a direct Pax3NCE2 activator and Cdx neural cofactor) as well as the maintenance of Pax3 dorsal restriction (as a target of the ventral Shh repressive input). We also provide evidence that the inductive Cdx-Zic2 interaction is integrated on NCE2 with a positive input from the neural-specific transcription factor Sox2. Altogether, our data provide important mechanistic insights into the coordinated integration of different signaling pathways on a short Pax3 CRM.
authors.affiliation: Molecular Genetics of Development Laboratory, Department of Biological Sciences and BioMed Research Center, Faculty of Sciences, University of Quebec at Montreal (UQAM), Canada.
authors.forename: Oraly
authors.initials: O
authors.lastname: Sanchez-Ferras
authors.affiliation: Molecular Genetics of Development Laboratory, Department of Biological Sciences and BioMed Research Center, Faculty of Sciences, University of Quebec at Montreal (UQAM), Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bernas
authors.affiliation: Molecular Genetics of Development Laboratory, Department of Biological Sciences and BioMed Research Center, Faculty of Sciences, University of Quebec at Montreal (UQAM), Canada.
authors.forename: Emilie
authors.initials: E
authors.lastname: Laberge-Perrault
authors.affiliation: Molecular Genetics of Development Laboratory, Department of Biological Sciences and BioMed Research Center, Faculty of Sciences, University of Quebec at Montreal (UQAM), Canada. Electronic address: pilon.nicolas@uqam.ca.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pilon
mesh_terms: D000818:Animals; D004742:Enhancer Elements, Genetic; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D006801:Humans; D051379:Mice; D009432:Neural Crest / Q000254:growth & development; D054259:Neural Tube / Q000254:growth & development* / Q000378:metabolism; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D055748:SOXB1 Transcription Factors / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D053823:Hedgehog Proteins; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D055748:SOXB1 Transcription Factors; C465570:Shh protein, mouse; C527783:Sox2 protein, mouse; C068686:Pax3 protein, mouse
keywords: Cdx; Neural crest cell; Neural tube; Pax3; Sox2; Zic