title: Endothelin signaling activates Mef2c expression in the neural crest through a MEF2C-dependent positive-feedback transcriptional pathway.
abstract: Endothelin signaling is essential for neural crest development, and dysregulated Endothelin signaling is associated with several neural crest-related disorders, including Waardenburg and other syndromes. However, despite the crucial roles of this pathway in neural crest development and disease, the transcriptional effectors directly activated by Endothelin signaling during neural crest development remain incompletely elucidated. Here, we establish that the MADS box transcription factor MEF2C is an immediate downstream transcriptional target and effector of Endothelin signaling in the neural crest. We show that Endothelin signaling activates Mef2c expression in the neural crest through a conserved enhancer in the Mef2c locus and that CRISPR-mediated deletion of this Mef2c neural crest enhancer from the mouse genome abolishes Endothelin induction of Mef2c expression. Moreover, we demonstrate that Endothelin signaling activates neural crest expression of Mef2c by de-repressing MEF2C activity through a Calmodulin-CamKII-histone deacetylase signaling cascade. Thus, these findings identify a MEF2C-dependent, positive-feedback mechanism for Endothelin induction and establish MEF2C as an immediate transcriptional effector and target of Endothelin signaling in the neural crest.
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA 94143, USA.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Hu
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA 94143, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Verzi
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA 94143, USA.
authors.forename: Ashley S
authors.initials: AS
authors.lastname: Robinson
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA 94143, USA.
authors.forename: Paul Ling-Fung
authors.initials: PL
authors.lastname: Tang
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA 94143, USA.
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Hua
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA 94143, USA.
authors.forename: Shan-Mei
authors.initials: SM
authors.lastname: Xu
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA 94143, USA Department of Dermatology, University of California, San Francisco, CA 94143, USA.
authors.forename: Pui-Yan
authors.initials: PY
authors.lastname: Kwok
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA 94143, USA Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143, USA brian.black@ucsf.edu.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Black
mesh_terms: D000818:Animals; D016232:Endothelins / Q000378:metabolism*; D025461:Feedback, Physiological / Q000502:physiology*; D005697:Galactosides; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D017403:In Situ Hybridization; D007211:Indoles; D064326:MEF2 Transcription Factors / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009432:Neural Crest / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D001616:beta-Galactosidase
chemical_list: D016232:Endothelins; D005697:Galactosides; D007211:Indoles; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D001616:beta-Galactosidase; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside
keywords: Craniofacial development; Endothelin; MEF2C; Melanocytes; Mouse; Neural crest; Transcription