Inactivation of LAR family phosphatase genesPtprsandPtprfcauses craniofacial malformations resembling Pierre-Robin sequence

Abstract

SUMMARYLeukocyte 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. Hendriks et al., 2013). LAR family phosphatases have been implicated in several key embryonic signaling pathways, including those involved in the negative regulation of growth factor receptors such as EGFR, RET and MET, and potentially modulate canonical Wnt/β-catenin signaling (Kypta et al., 1996;Müller et al., 1999;Tisi et al., 2000;Wang et al., 2000; Ensslen-Craig and BradyKalnay, 2004;Machide et al., 2006;Haapasalo et al., 2007;Uetani et al., 2009;Zheng et al., 2011). Although LAR family phosphatases are expressed in several embryonic and adult tissues (Schaapveld et al., 1998), mice mutant for single family members generally survive to adulthood, reflecting a functional redundancy within the family (Schaapveld et al., 1997; Elchebly et al., 1999;Wallace et al., 1999;Uetani et al., 2000;Thompson et al., 2003;Wang et al., 2011). Accordingly, Ptprd;Ptprs double-mutant embryos show defects in motoneuron innervation (Uetani et al., 2006), whereas Ptprs;Ptprf double-mutants harbor severe urogenital and craniofacial defects (Uetani et al., 2009). Although micrognathia and cleft palate were noted in approximately half of Ptprs;Ptprf double-knockout (DKO) embryos at embryonic day (E) 18.5 (Uetani et al., 2009), the molecular and cellular basis for this phenotype was not investigated further. In this study, we demonstrate that Ptprs and Ptprf are necessary for mandibular morphogenesis through the regulation of Wnt and Bmp signaling, and that their absence results in a phenotype closely resembling PRS. KEY WORDS: LAR phosphatases MATERIALS AND METHODS MiceThe derivation of genetically modified Ptprs;Ptprf mice has b...

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