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Pituitary, Pancreatic and Gut Neuroendocrine Defects in Protein Tyrosine Phosphatase- Sigma-Deficient Mice

The Hospital for Sick Children (J.B., C.F., D.R.), Program in Cell Biology, and Institute of Medical Science and Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada, M5G 1X8; and Departments of Pathology (S.A.), University of Toronto and Laboratory Medicine and Pathobiology, University Health Network, Toronto, Ontario, Canada, M5G 2C4

Address all correspondence and requests for reprints to: Dr. Daniela Rotin, Program in Cell Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada, M5G 1X8. E-mail: drotin{at}sickkids.on.ca

The expression of receptor protein tyrosine phosphatase sigma (PTP) is developmentally regulated in neuronal and neuroendocrine tissues. We have previously shown that mice deficient in PTP demonstrate nervous system abnormalities, pituitary hypoplasia, increased neonatal mortality (60%), and death from a wasting syndrome at 2–3 wk of age (38%). We have now examined the role of PTP on pituitary, pancreas and enteroendocrine cytodifferentiation, hormone production, and development. The adenohypophyses of PTP(-/-) mice were small and exhibited reduced GH and PRL immunoreactivity. Cells containing TSH, LH, FSH, ACTH, pituitary-specific POU homeodomain factor (Pit-1), ER, and steroidogenic factor 1 were found in normal proportions and distributions. The diminished expression of GH and PRL was not associated with apoptosis of somatotrophs or lactotrophs. Pit-1-positive TSH-negative cells were detected, suggesting that impaired GH and PRL synthesis was not attributable to Pit-1 deficiency. In the knockout mice, pancreatic islets were hypoplastic with reduced insulin immunoreactivity, and there was also variable expression of gut hormones. Functionally, the GH deficiency was associated with hypoglycemia and death in the PTP(-/-) neonate and accordingly, ip administration of GH rescued the PTP(-/-) neonate and normalized the blood glucose. These data indicate that PTP plays a major role in differentiation and development of the neuroendocrine system.

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