title: Nkx2.5 regulates endothelin converting enzyme-1 during pharyngeal arch patterning.
abstract: In gnathostomes, dorsoventral (D-V) patterning of neural crest cells (NCC) within the pharyngeal arches is crucial for the development of hinged jaws. One of the key signals that mediate this process is Endothelin-1 (EDN1). Loss of EDN1 binding to the Endothelin-A receptor (EDNRA) results in loss of EDNRA signaling and subsequent facial birth defects in humans, mice and zebrafish. A rate-limiting step in this crucial signaling pathway is the conversion of immature EDN1 into a mature active form by Endothelin converting enzyme-1 (ECE1). However, surprisingly little is known about how Ece1 transcription is induced or regulated. We show here that Nkx2.5 is required for proper craniofacial development in zebrafish and acts in part by upregulating ece1 expression. Disruption of nkx2.5 in zebrafish embryos results in defects in both ventral and dorsal pharyngeal arch-derived elements, with changes in ventral arch gene expression consistent with a disruption in Ednra signaling. ece1 mRNA rescues the nkx2.5 morphant phenotype, indicating that Nkx2.5 functions through modulating Ece1 expression or function. These studies illustrate a new function for Nkx2.5 in embryonic development and provide new avenues with which to pursue potential mechanisms underlying human facial disorders.
authors.affiliation: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, 80045.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Iklé
authors.affiliation: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, 80045.
authors.forename: Andre L P
authors.initials: AL
authors.lastname: Tavares
authors.affiliation: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, 80045.
authors.forename: Marisol
authors.initials: M
authors.lastname: King
authors.affiliation: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, 80045.
authors.forename: Hailei
authors.initials: H
authors.lastname: Ding
authors.affiliation: Division of Cardiology, Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, 10032.
authors.forename: Sophie
authors.initials: S
authors.lastname: Colombo
authors.affiliation: Departments of Anatomy and Medical, Biochemistry, and Molecular Genetics, Indiana Medical School, Riley Heart Research Center, Herman B Wells Center for Pediatric Research, Division of Pediatric Cardiology, Indianapolis, 46202.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Firulli
authors.affiliation: Departments of Anatomy and Medical, Biochemistry, and Molecular Genetics, Indiana Medical School, Riley Heart Research Center, Herman B Wells Center for Pediatric Research, Division of Pediatric Cardiology, Indianapolis, 46202.
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Firulli
authors.affiliation: Division of Cardiology, Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, 10032.
authors.forename: Kimara L
authors.initials: KL
authors.lastname: Targoff
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, California, 92093.
authors.forename: Deborah
authors.initials: D
authors.lastname: Yelon
authors.affiliation: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, 80045.
authors.forename: David E
authors.identifier: 0000-0002-2008-477X
authors.initials: DE
authors.lastname: Clouthier
mesh_terms: D000818:Animals; D000072396:Endothelin-Converting Enzymes / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D000072576:Homeobox Protein Nkx-2.5 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009432:Neural Crest / Q000196:embryology / Q000378:metabolism*; D010614:Pharynx / Q000196:embryology / Q000378:metabolism; D015854:Up-Regulation; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000072576:Homeobox Protein Nkx-2.5; C528182:Nkx2.5 protein, zebrafish; D029961:Zebrafish Proteins; D000072396:Endothelin-Converting Enzymes
keywords: birth defects; neural crest; patterning; signaling; transcription