title: Neural crest development and craniofacial morphogenesis is coordinated by nitric oxide and histone acetylation.
abstract: Cranial neural crest (CNC) cells are patterned and coalesce to facial prominences that undergo convergence and extension to generate the craniofacial form. We applied a chemical genetics approach to identify pathways that regulate craniofacial development during embryogenesis. Treatment with the nitric oxide synthase inhibitor 1-(2-[trifluoromethyl] phenyl) imidazole (TRIM) abrogated first pharyngeal arch structures and induced ectopic ceratobranchial formation. TRIM promoted a progenitor CNC fate and inhibited chondrogenic differentiation, which were mediated through impaired nitric oxide (NO) production without appreciable effect on global protein S-nitrosylation. Instead, TRIM perturbed hox gene patterning and caused histone hypoacetylation. Rescue of TRIM phenotype was achieved with overexpression of histone acetyltransferase kat6a, inhibition of histone deacetylase, and complementary NO. These studies demonstrate that NO signaling and histone acetylation are coordinated mechanisms that regulate CNC patterning, differentiation, and convergence during craniofacial morphogenesis.
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Division of Plastic and Reconstructive Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Shriners Hospitals for Children, Boston, MA 02114, USA.
authors.forename: Yawei
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Division of Plastic and Reconstructive Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Shriners Hospitals for Children, Boston, MA 02114, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Grimaldi
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Division of Plastic and Reconstructive Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Curtin
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Division of Plastic and Reconstructive Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Max
authors.initials: M
authors.lastname: Dougherty
authors.affiliation: Howard Hughes Medical Institute, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Kaufman
authors.affiliation: Howard Hughes Medical Institute, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: White
authors.affiliation: Howard Hughes Medical Institute, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Boston, MA 02114, USA.
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Division of Plastic and Reconstructive Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Shriners Hospitals for Children, Boston, MA 02114, USA; Harvard Stem Cell Institute, Boston, MA 02114, USA. Electronic address: cliao@partners.org.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Liao
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D020219:Chondrogenesis / Q000187:drug effects; D006657:Histones / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D009024:Morphogenesis / Q000187:drug effects; D009432:Neural Crest / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015027:Zebrafish / Q000196:embryology* / Q000378:metabolism*
chemical_list: D006657:Histones; D007093:Imidazoles; C098186:1-(2-trifluoromethylphenyl)imidazole; D009569:Nitric Oxide