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Neuronal defects and posterior pituitary hypoplasia in mice lacking the receptor tyrosine phosphatase PTPσ

Abstract

The LAR-family protein tyrosine phosphatase σ (PTPσ, encoded by the gene Ptprs) consists of a cell adhesion-like extracellular domain composed of immunoglobulin and fibronectin type-III repeats, a single transmembrane domain and two intracellular catalytic domains1,2. It was previously shown to be expressed in neuronal and lung epithelial tissues in a developmentally regulated manner2,3,4,5,6,7,8. To study the role of PTPσ in mouse development, we inactivated Ptprs by gene targeting. All Ptprs+/– mice developed normally, whereas 60% of Ptprs–/– mice died within 48 hours after birth. The surviving Ptprs–/– mice demonstrated stunted growth, developmental delays and severe neurological defects including spastic movements, tremor, ataxic gait, abnormal limb flexion and defective proprioception. Histopathology of brain sections revealed reduction and hypocellularity of the posterior pituitary of Ptprs–/– mice, as well as a reduction of approximately 50-75% in the number of choline acetyl transferase-positive cells in the forebrain. Moreover, peripheral nerve electrophysiological analysis revealed slower conduction velocity in Ptprs–/– mice relative to wild-type or heterozygous animals, associated with an increased proportion of slowly conducting, small-diameter myelinated fibres and relative hypomyelination. By approximately three weeks of age, most remaining Ptprs–/– mice died from a wasting syndrome with atrophic intestinal villi. These results suggest that PTPσ has a role in neuronal and epithelial development in mice.

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Figure 1: Generation of Ptprs–/– mice.
Figure 2: Histopathology of lung, intestine and pituitary gland of Ptprs–/– mice.
Figure 3: Growth retardation and abnormal limb flexion in Ptprs–/– mice.
Figure 4: Abnormal peripheral nerve conduction velocity and myelinated fibre size.
Figure 5: Reduction in numbers of cholinergic neurons in the forebrain analysed by ChAT staining.

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Acknowledgements

We thank C. McKerlie for histopathology analyses; J. Bain for assistance with nerve conduction analyses; B. Goldstein for Ptprs cDNA; J. Rossant for 129 genomic DNA library; and D. Hunter for assistance with the peripheral nerve morphometric analysis. This work was supported by a Group Grant in Lung Development from the Medical Research Council (MRC) of Canada (to D.R.). D.R. was a recipient of an MRC Scholarship. M.J.W. was supported by Canadian Lung Association/MRC Fellowships. J.B. is a recipient of an MRC Fellowship.

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Wallace, M., Batt, J., Fladd, C. et al. Neuronal defects and posterior pituitary hypoplasia in mice lacking the receptor tyrosine phosphatase PTPσ. Nat Genet 21, 334–338 (1999). https://doi.org/10.1038/6866

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