title: The extreme anterior domain is an essential craniofacial organizer acting through Kinin-Kallikrein signaling.
abstract: The extreme anterior domain (EAD) is a conserved embryonic region that includes the presumptive mouth. We show that the Kinin-Kallikrein pathway is active in the EAD and necessary for craniofacial development in Xenopus and zebrafish. The mouth failed to form and neural crest (NC) development and migration was abnormal after loss of function (LOF) in the pathway genes kng, encoding Bradykinin (xBdk), carboxypeptidase-N (cpn), which cleaves Bradykinin, and neuronal nitric oxide synthase (nNOS). Consistent with a role for nitric oxide (NO) in face formation, endogenous NO levels declined after LOF in pathway genes, but these were restored and a normal face formed after medial implantation of xBdk-beads into LOF embryos. Facial transplants demonstrated that Cpn function from within the EAD is necessary for the migration of first arch cranial NC into the face and for promoting mouth opening. The study identifies the EAD as an essential craniofacial organizer acting through Kinin-Kallikrein signaling.
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA; Massachusetts Institute of Technology, 77 Massachusetts Ave, Cambridge, MA 02139, USA; Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA; Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115, USA; Harvard Graduate School of Arts and Sciences, 1350 Massachusetts Avenue, Holyoke Center, 50, Cambridge, MA 02138, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Jacox
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Radek
authors.initials: R
authors.lastname: Sindelka
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA; Massachusetts Institute of Technology, 77 Massachusetts Ave, Cambridge, MA 02139, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Chen
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Rothman
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Dickinson
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA; Massachusetts Institute of Technology, 77 Massachusetts Ave, Cambridge, MA 02139, USA. Electronic address: sive@wi.mit.edu.
authors.forename: Hazel
authors.initials: H
authors.lastname: Sive
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000378:metabolism; D002268:Carboxypeptidases / Q000378:metabolism; D016234:Kallikrein-Kinin System; D009055:Mouth / Q000196:embryology*; D009432:Neural Crest / Q000196:embryology* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D015398:Signal Transduction; D014981:Xenopus; D015027:Zebrafish
chemical_list: D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D002268:Carboxypeptidases; D001920:Bradykinin