title: Hand1 phosphoregulation within the distal arch neural crest is essential for craniofacial morphogenesis.
abstract: In this study we examine the consequences of altering Hand1 phosphoregulation in the developing neural crest cells (NCCs) of mice. Whereas Hand1 deletion in NCCs reveals a nonessential role for Hand1 in craniofacial development and embryonic survival, altering Hand1 phosphoregulation, and consequently Hand1 dimerization affinities, in NCCs results in severe mid-facial clefting and neonatal death. Hand1 phosphorylation mutants exhibit a non-cell-autonomous increase in pharyngeal arch cell death accompanied by alterations in Fgf8 and Shh pathway expression. Together, our data indicate that the extreme distal pharyngeal arch expression domain of Hand1 defines a novel bHLH-dependent activity, and that disruption of established Hand1 dimer phosphoregulation within this domain disrupts normal craniofacial patterning.
authors: Riley Heart Research Center, Herman B Wells Center for Pediatric Research, Division of Pediatric Cardiology, Departments of Anatomy and Medical, Biochemistry, and Molecular Genetics, Indiana Medical School, 1044 W. Walnut Street, Indianapolis, IN 46202-5225, USA.
authors: Beth A
authors: BA
authors: Firulli
authors: Department of Physical Therapy and the Center for Translational Musculoskeletal Research, School of Health and Rehabilitation Science, Indiana University, Indianapolis, IN 46202, USA.
authors: Robyn K
authors: RK
authors: Fuchs
authors: Riley Heart Research Center, Herman B Wells Center for Pediatric Research, Division of Pediatric Cardiology, Departments of Anatomy and Medical, Biochemistry, and Molecular Genetics, Indiana Medical School, 1044 W. Walnut Street, Indianapolis, IN 46202-5225, USA.
authors: Joshua W
authors: JW
authors: Vincentz
authors: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, 12801 E 17th Avenue, Rm. 11-109, MS 8120, Aurora, CO 80045, USA.
authors: David E
authors: DE
authors: Clouthier
authors: Riley Heart Research Center, Herman B Wells Center for Pediatric Research, Division of Pediatric Cardiology, Departments of Anatomy and Medical, Biochemistry, and Molecular Genetics, Indiana Medical School, 1044 W. Walnut Street, Indianapolis, IN 46202-5225, USA tfirulli@iupui.edu.
authors: Anthony B
authors: AB
authors: Firulli
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019521:Body Patterning / Q000235:genetics; D001934:Branchial Region / Q000378:metabolism; D005145:Face / Q000196:embryology; D005260:Female; D051524:Fibroblast Growth Factor 8 / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D053823:Hedgehog Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D009024:Morphogenesis / Q000502:physiology; D009154:Mutation; D009432:Neural Crest / Q000196:embryology*; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D010766:Phosphorylation; D055503:Protein Multimerization; D015398:Signal Transduction; D012886:Skull / Q000196:embryology*; D051879:Twist-Related Protein 1 / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051524:Fibroblast Growth Factor 8; D053823:Hedgehog Proteins; D009687:Nuclear Proteins; D051879:Twist-Related Protein 1; C496457:Fgf8 protein, mouse; C095572:Hand1 protein, mouse; C465570:Shh protein, mouse; C067250:Twist1 protein, mouse
keywords: Craniofacial development; Dimerization; Hand1; Neural crest; Phosphorylation; Transcription; bHLH