title: Downregulation of Dlx5 and Dlx6 expression by Hand2 is essential for initiation of tongue morphogenesis.
abstract: Lower jaw development is a complex process in which multiple signaling cascades establish a proximal-distal organization. These cascades are regulated both spatially and temporally and are constantly refined through both induction of normal signals and inhibition of inappropriate signals. The connective tissue of the tongue arises from cranial neural crest cell-derived ectomesenchyme within the mandibular portion of the first pharyngeal arch and is likely to be impacted by this signaling. Although the developmental mechanisms behind later aspects of tongue development, including innervation and taste acquisition, have been elucidated, the early patterning signals driving ectomesenchyme into a tongue lineage are largely unknown. We show here that the basic helix-loop-helix transcription factor Hand2 plays key roles in establishing the proximal-distal patterning of the mouse lower jaw, in part through establishing a negative-feedback loop in which Hand2 represses Dlx5 and Dlx6 expression in the distal arch ectomesenchyme following Dlx5- and Dlx6-mediated induction of Hand2 expression in the same region. Failure to repress distal Dlx5 and Dlx6 expression results in upregulation of Runx2 expression in the mandibular arch and the subsequent formation of aberrant bone in the lower jaw along with proximal-distal duplications. In addition, there is an absence of lateral lingual swelling expansion, from which the tongue arises, resulting in aglossia. Hand2 thus appears to establish a distal mandibular arch domain that is conducive for lower jaw development, including the initiation of tongue mesenchyme morphogenesis.
authors.affiliation: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Francie
authors.initials: F
authors.lastname: Barron
authors.forename: Crystal
authors.initials: C
authors.lastname: Woods
authors.forename: Katherine
authors.initials: K
authors.lastname: Kuhn
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bishop
authors.forename: Marthe J
authors.initials: MJ
authors.lastname: Howard
authors.forename: David E
authors.initials: DE
authors.lastname: Clouthier
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D019521:Body Patterning; D001842:Bone and Bones / Q000196:embryology; D002460:Cell Line; D049109:Cell Proliferation; D050659:Core Binding Factor Alpha 1 Subunit / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics*; D017403:In Situ Hybridization; D007568:Jaw / Q000196:embryology; D051379:Mice; D018345:Mice, Knockout; D009432:Neural Crest / Q000166:cytology / Q000378:metabolism; D038081:Organogenesis; D016133:Polymerase Chain Reaction; D015398:Signal Transduction; D014059:Tongue / Q000196:embryology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D018398:Homeodomain Proteins; C501120:Dlx5 protein, mouse; C100597:Dlx6 protein, mouse; C498766:Hand2 protein, mouse; C493716:Runx2 protein, mouse