title: Inactivation of LAR family phosphatase genes Ptprs and Ptprf causes craniofacial malformations resembling Pierre-Robin sequence.
abstract: Leukocyte antigen related (LAR) family receptor protein tyrosine phosphatases (RPTPs) regulate the fine balance between tyrosine phosphorylation and dephosphorylation that is crucial for cell signaling during development and tissue homeostasis. Here we show that LAR RPTPs are required for normal development of the mandibular and maxillary regions. Approximately half of the mouse embryos lacking both Ptprs (RPTPσ) and Ptprf (LAR) exhibit micrognathia (small lower jaw), cleft palate and microglossia/glossoptosis (small and deep tongue), a phenotype closely resembling Pierre-Robin sequence in humans. We show that jaw bone and cartilage patterning occurs aberrantly in LAR family phosphatase-deficient embryos and that the mandibular arch harbors a marked decrease in cell proliferation. Analysis of signal transduction in embryonic tissues and mouse embryonic fibroblast cultures identifies an increase in Bmp-Smad signaling and an abrogation of canonical Wnt signaling associated with loss of the LAR family phosphatases. A reactivation of β-catenin signaling by chemical inhibition of GSK3β successfully resensitizes LAR family phosphatase-deficient cells to Wnt induction, indicating that RPTPs are necessary for normal Wnt/β-catenin pathway activation. Together these results identify LAR RPTPs as important regulators of craniofacial morphogenesis and provide insight into the etiology of Pierre-Robin sequence.
authors.affiliation: Goodman Cancer Research Centre, Department of Biochemistry, McGill University, Montreal, 1160 Pine Avenue W. Montreal, QC H3A 1A3, Canada.
authors.forename: Katherine
authors.initials: K
authors.lastname: Stewart
authors.forename: Noriko
authors.initials: N
authors.lastname: Uetani
authors.forename: Wiljan
authors.initials: W
authors.lastname: Hendriks
authors.forename: Michel L
authors.initials: ML
authors.lastname: Tremblay
authors.forename: Maxime
authors.initials: M
authors.lastname: Bouchard
mesh_terms: D000818:Animals; D060466:Axin Protein / Q000235:genetics / Q000378:metabolism; D019521:Body Patterning; D001846:Bone Development; D049109:Cell Proliferation; D002478:Cells, Cultured; D002972:Cleft Palate / Q000201:enzymology / Q000473:pathology; D004622:Embryo, Mammalian / Q000201:enzymology / Q000473:pathology; D005347:Fibroblasts / Q000201:enzymology; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D020868:Gene Silencing; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D007211:Indoles / Q000494:pharmacology; D008648:Mesoderm; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008844:Micrognathism / Q000201:enzymology / Q000473:pathology; D010091:Oximes / Q000494:pharmacology; D010855:Pierre Robin Syndrome / Q000201:enzymology* / Q000473:pathology; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: C579143:3,6-bromoindirubin 3'-oxime; D060466:Axin Protein; C111729:Axin2 protein, mouse; D007211:Indoles; D010091:Oximes; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; C000709129:Ptprf protein, mouse; C516885:Ptprs protein, mouse; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2
keywords: Bmp; Craniofacial development; LAR phosphatases; Mouse; Pierre-Robin sequence; Wnt