Inactivation of LAR family phosphatase genes Ptprs and Ptprf causes craniofacial malformations resembling Pierre-Robin sequence

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 (RPTPs) 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 beta-catenin signaling by chemical inhibition of GSK3 beta successfully resensitizes LAR family phosphatase-deficient cells to Wnt induction, indicating that RPTPs are necessary for normal Wnt/beta-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.