Characterization of the role of protein tyrosine phosphatase sigma (PTPsigma) in mammalian development

Protein tyrosine phosphatase sigma (PTPsigma) is a member of the mammalian LAR family of phosphatases, which consists of three closely related proteins LAR, PTPdelta and PTPsigma. These phosphatases contain a cell adhesion molecule (CAM)-like ectodomain, a single pass transmembrane domain and two tandemly repeated intracellular phosphatase domains; the N terminal domain (D1) is catalytically active, and the C terminal domain (D2) is inactive. PTPsigma expression is developmentally regulated in neuronal and epithelial tissues, and the PTPsigma/PTPdelta/LAR Drosophila homologue DLAR plays a crucial role in axonal pathfinding, which led us to speculate that PTPsigma may serve an important function in the development of the mammalian nervous system, epithelialized tissues and organs.; To study the role of PTPsigma in mammalian development we generated and characterized full-length PTPsigma knockout mice. The loss of the PTPsigma protein results in abnormalities of the neuroendocrine, central and peripheral nervous systems. PTPsigma(-/-) mice display pituitary hypoplasia, growth hormone (GH) and prolactin deficiencies. Functionally, the GH deficiency contributes to hypoglycemia and a high neonatal mortality rate, pancreatic islet hypoplasia and hypoinsulinemia. PTPsigma deficient animals also display an altered glucose homeostasis. While the CNS of PTPsigma(-/-) mice demonstrates the subtle abnormality of decreased choline acetyltransferase (ChAT) immunostaining, the PNS shows marked developmental delay and striking changes in regenerative growth. The loss of PTPsigma increases the rate of sciatic nerve regeneration following injury, and results in significant axonal guidance errors. The lung, an epithelialized organ which strongly expresses PTPsigma, appeared architecturally normal in the PTPsigma(-/-) mice. We speculate that normal pulmonary development in the absence of PTPsigma results from the compensatory action of the closely related LAR.; The molecular mechanism by which the loss of PTPsigma results in these abnormalities is not known. We demonstrated that the binding of PTPdeltaD2 to PTPsigmaD1 down regulates the catalytic activity of PTPsigma, and suggested that heterodimerization may serve as a means by which to regulate the catalytic phosphatase activity of this family of enzymes. However, the target substrate(s) and signalling pathways in which PTPsigma partakes remain unknown.; In summary, PTPsigma plays a crucial role in the development of mammalian neuroendocrine and neurologic systems.