title: Pax3 and hippo signaling coordinate melanocyte gene expression in neural crest.
abstract: Loss of Pax3, a developmentally regulated transcription factor expressed in premigratory neural crest, results in severe developmental defects and embryonic lethality. Although Pax3 mutations produce profound phenotypes, the intrinsic transcriptional activation exhibited by Pax3 is surprisingly modest. We postulated the existence of transcriptional coactivators that function with Pax3 to mediate developmental functions. A high-throughput screen identified the Hippo effector proteins Taz and Yap65 as Pax3 coactivators. Synergistic coactivation of target genes by Pax3-Taz/Yap65 requires DNA binding by Pax3, is Tead independent, and is regulated by Hippo kinases Mst1 and Lats2. In vivo, Pax3 and Yap65 colocalize in the nucleus of neural crest progenitors in the dorsal neural tube. Neural crest deletion of Taz and Yap65 results in embryo-lethal neural crest defects and decreased expression of the Pax3 target gene, Mitf. These results suggest that Pax3 activity is regulated by the Hippo pathway and that Pax factors are Hippo effectors.
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Lauren J
authors.initials: LJ
authors.lastname: Manderfield
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Engleka
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Haig
authors.initials: H
authors.lastname: Aghajanian
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Mudit
authors.initials: M
authors.lastname: Gupta
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Baggs
authors.affiliation: Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: John B
authors.initials: JB
authors.lastname: Hogenesch
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: epsteinj@mail.med.upenn.edu.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Epstein
mesh_terms: D000818:Animals; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D057809:HEK293 Cells; D000090683:Hippo Signaling Pathway; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008544:Melanocytes / Q000378:metabolism*; D008822:Mice, Transgenic; D009432:Neural Crest / Q000166:cytology*; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport; D015533:Transcriptional Activation
chemical_list: D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; C068686:Pax3 protein, mouse; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases