title: Exclusion of Dlx5/6 expression from the distal-most mandibular arches enables BMP-mediated specification of the distal cap.
abstract: Cranial neural crest cells (crNCCs) migrate from the neural tube to the pharyngeal arches (PAs) of the developing embryo and, subsequently, differentiate into bone and connective tissue to form the mandible. Within the PAs, crNCCs respond to local signaling cues to partition into the proximo-distally oriented subdomains that convey positional information to these developing tissues. Here, we show that the distal-most of these subdomains, the distal cap, is marked by expression of the transcription factor Hand1 (H1) and gives rise to the ectomesenchymal derivatives of the lower incisors. We uncover a H1 enhancer sufficient to drive reporter gene expression within the crNCCs of the distal cap. We show that bone morphogenic protein (BMP) signaling and the transcription factor HAND2 (H2) synergistically regulate H1 distal cap expression. Furthermore, the homeodomain proteins distal-less homeobox 5 (DLX5) and DLX6 reciprocally inhibit BMP/H2-mediated H1 enhancer regulation. These findings provide insights into how multiple signaling pathways direct transcriptional outcomes that pattern the developing jaw.
authors.affiliation: Riley Heart Research Center, Herman B. Wells Center for Pediatric Research Division of Pediatric Cardiology, Departments of Anatomy, Biochemistry, and Medical and Molecular Genetics, Indiana University Medical School, Indianapolis, IN 46202;
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Vincentz
authors.affiliation: Riley Heart Research Center, Herman B. Wells Center for Pediatric Research Division of Pediatric Cardiology, Departments of Anatomy, Biochemistry, and Medical and Molecular Genetics, Indiana University Medical School, Indianapolis, IN 46202;
authors.forename: Jose J
authors.initials: JJ
authors.lastname: Casasnovas
authors.affiliation: Biologics Discovery California, Bristol-Myers Squibb, Redwood City, CA 94063;
authors.forename: Ralston M
authors.initials: RM
authors.lastname: Barnes
authors.affiliation: Department of Medicine, Columbia University Medical Center, New York, NY 10032;
authors.forename: Jianwen
authors.initials: J
authors.lastname: Que
authors.affiliation: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80108;
authors.forename: David E
authors.initials: DE
authors.lastname: Clouthier
authors.affiliation: Department of Molecular Physiology and Biophysics, Texas Heart Institute, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Riley Heart Research Center, Herman B. Wells Center for Pediatric Research Division of Pediatric Cardiology, Departments of Anatomy, Biochemistry, and Medical and Molecular Genetics, Indiana University Medical School, Indianapolis, IN 46202; tfirulli@iu.edu.
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Firulli
mesh_terms: D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D050980:GATA Transcription Factors / Q000378:metabolism; D017930:Genes, Reporter; D018398:Homeodomain Proteins / Q000378:metabolism*; D008334:Mandible / Q000196:embryology* / Q000378:metabolism; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019485:Bone Morphogenetic Proteins; D050980:GATA Transcription Factors; D018398:Homeodomain Proteins; D051785:Smad Proteins; C501120:Dlx5 protein, mouse; C100597:Dlx6 protein, mouse; C095572:Hand1 protein, mouse; C498766:Hand2 protein, mouse
keywords: Bmp; DLX; HAND1; cranial neural crest cells; development