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Neuroendocrine dysplasia in mice lacking protein tyrosine phosphatase σ

Abstract

Protein tyrosine phosphatase σ (PTP-σ, encoded by the Ptprs gene) is a member of the LAR subfamily of receptor-like protein tyrosine phosphatases that is highly expressed during mammalian embryonic development in the germinal cell layer lining the lateral ventricles of the developing brain, dorsal root ganglia, Rathke's pouch, olfactory epithelium, retina and developing lung and heart1,2,3,4. On the basis of its expression and homology with the Drosophila melanogaster orthologues DPTP99 and DPTP100A (Refs 5,6), which have roles in the targeting of axonal growth cones, we hypothesized that PTP-σ may also have a modulating function in cell-cell interactions, as well as in axon guidance during mammalian embryogenesis. To investigate its function in vivo, we generated Ptprs-deficient mice. The resulting Ptprs-/- animals display retarded growth, increased neonatal mortality, hyposmia and hypofecundity. Anatomical and histological analyses showed a decrease in overall brain size with a severe depletion of luteinizing hormone-releasing hormone (LHRH)-immunoreactive cells in Ptprs-/- hypothalamus. Ptprs-/- mice have an enlarged intermediate pituitary lobe, but smaller anterior and posterior lobes. These results suggest that tyrosine phosphorylation-dependent signalling pathways regulated by PTP-σ influence the proliferation and/or adhesiveness of various cell types in the developing hypothalamo-pituitary axis.

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Figure 1: Gene targeting of mouse Ptprs.
Figure 2: Reduced size of the olfactory bulbs in Ptprs-/- animals compared with wild-type olfactory bulbs (a).
Figure 3: Pituitary dysplasia in Ptprs-/- animals.
Figure 4: Developmental analysis of wild-type and Ptprs-/- pituitary.
Figure 5: Immunohistological analysis of wild-type and Ptprs-/- pituitary.
Figure 6: Immunohistological analysis of wild-type and Ptprs-/- hypothalamus.

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Acknowledgements

We thank K.A. Mahon for fruitful discussions; H.H. Zingg for helpful comments on the manuscript; and members of the Tremblay lab for discussions and assistance. M.E. is a fellowship recipient of the Canderel Foundation and the Fonds de la Recherche en Santé du Québec (FRSQ). T.E.K. is a scholar of the Medical Research Council of Canada. J.D. is a recipient of a National Cancer Institute of Canada operating grant. M.L.T. is a Chercheur-Boursier from the FRSQ. This study was supported by a grant to M.L.T. from the Cancer Research Society Inc.

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Correspondence to Michel L. Tremblay.

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Elchebly, M., Wagner, J., Kennedy, T. et al. Neuroendocrine dysplasia in mice lacking protein tyrosine phosphatase σ. Nat Genet 21, 330–333 (1999). https://doi.org/10.1038/6859

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