Identification of minimal enhancer elements sufficient for Pax3 expression in neural crest and implication of Tead2 as a regulator of Pax3.
Pax3 is a transcription factor that is required by pre-migratory neural crest cells, which give rise to the peripheral nervous system, melanocytes, some vascular smooth muscle, and numerous other derivatives [corrected]. Both mice and humans with Pax3 deficiency exhibit neural crest-related developmental defects [corrected]. Pax3 is also expressed in the dorsal neural tube, and by myogenic progenitors in the presomitic mesoderm and the hypaxial somites. Molecular pathways that regulate Pax3 expression in the roof plate probably represent early upstream signals in neural crest induction. We have identified an enhancer region in the Pax3 genomic locus that is sufficient to recapitulate expression in neural crest precursors in transgenic mice. We show that Tead2, a member of the Tead box family of transcription factors, binds to a neural crest enhancer and activates Pax3 expression. Tead2, and its co-activator YAP65, are co-expressed with Pax3 in the dorsal neural tube, and mutation of the Tead2 binding site in the context of Pax3 transgenic constructs abolishes neural expression. In addition, a Tead2-Engrailed fusion protein is able to repress retinoic acid-induced Pax3 expression in P19 cells and in vivo. These results suggest that Tead2 is an endogenous activator of Pax3 in neural crest.
Milewski
Rita C
RC
Cardiovascular Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Chi
Neil C
NC
Li
Jun
J
Brown
Christopher
C
Lu
Min Min
MM
Epstein
Jonathan A
JA
D000818:Animals; D002490:Central Nervous System / Q000196:embryology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008822:Mice, Transgenic; D009432:Neural Crest / Q000196:embryology* / Q000378:metabolism; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D011401:Promoter Regions, Genetic; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D019076:Transgenes
D004268:DNA-Binding Proteins; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D000091262:TEA Domain Transcription Factors; C486310:Tead2 protein, mouse; D014157:Transcription Factors; C068686:Pax3 protein, mouse