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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References
Zhang, W.-R., Hashimoto, H., Ahmad, F., Ding, W. & Goldstein, B.J. Molecular cloning and expression of a unique receptor-like protein tyrosine phosphatase in the leukocyte-common-antigen-related phosphatase family. Biochem. J. 302, 39– 47 (1994).
Yan, H. et al. A novel receptor tyrosine phosphatase-σ that is highly expressed in the nervous system. J. Biol. Chem. 268, 24880–24886 (1993).
Sahin, M. & Hockfield, M. Protein tyrosine phosphatases expressed in the developing rat brain. J. Neurosci. 13, 4968–4978 (1993).
Walton, K.M., Martell, K.J., Kwak, S.P., Dixon, J.E. & Largent, B.L. A novel receptor-type protein tyrosine phosphatase is expressed during neurogenesis in the olfactory neuroepithelium. Neuron 11, 387–400 (1993).
Stoker, A.W., Gehring, B., Haj, F. & Bay, B.H. Axonal localisation of the CAM-like tyrosine phosphatase CRYPα: a signalling molecule of embryonic growth cones. Development. 121, 1833– 1844 (1995).
Wang, H. et al. Expression of receptor protein tyrosine phosphatase-σ (RPTP-σ) in the nervous system of the developing and adult rat. J. Neurosci. Res. 41, 297–310 (1995).
Kim, H. et al. Expression of LAR-PTP2 in rat lung is confined to proliferating epithelia lining the airways and air sacs. Am. J. Physiol. 14, L566–576 (1996).
Haworth, K., Shu, K.K., Stokes, A., Morris, R. & Stokes, A. The expression of receptor tyrosine phosphatases is responsive to sciatic nerve crush. Mol. Cell. Neurosci. 12, 93–104 (1998).
Bourbon, J.R. & Fraslon, C. Developmental aspects of the alveolar epithelium and pulmonary surfactant system. in Pulmonary Surfactant: Biochemical, Functional, Regulatory and Clinical Concepts (ed. Bourbon, J.R.) 257–324 (CRC Press, New York, 1996).
Pitkanen, O. & O'Brodovich, H. Significance of ion transport during lung development and in respiratory disease of the newborn. Ann. Med. 30, 134–142 (1997).
Côté, F., Collard, J.-F. & Julien, J.-P. Progressive neuropathy in transgenic mice expressing the human neurofilament heavy gene: a mouse model for amyotrophic lateral sclerosis. Cell 73, 35– 46 (1993).
Desai, C.J., Gindhart, J.G. Jr, Goldstein, L.S.B. & Zinn, K. Receptor tyrosine phosphatases are required for motor axon guidance in the Drosophila embryo. Cell 84, 599– 609 (1996).
Krueger, N.X. et al. The transmembrane tyrosine phosphatase DLAR controls motor axon guidance in Drosophila. Cell 84, 611 –622 (1996).
Skarnes, W.C., Moss, J.E., Hurtley, S.M. & Beddington, R. Capturing genes encoding membrane and secreted proteins important for mouse development. Proc. Natl Acad. Sci. USA 92, 6592–6596 (1995).
Schaapveld, R.Q.J. et al. Impaired mammary gland development and function in mice lacking LAR receptor-like tyrosine phosphatase activity. Dev. Biol. 188, 134–146 (1995).
Yeo, T.T. et al. Deficient LAR expression decreases basal forebrain cholinergic neuronal size and hippocampal cholinergic innervation. J. Neurosci. Res. 47, 348–360 (1997).
Sommer, L., Rao, M. & Anderson, D.J. RPTPδ and the novel tyrosine phosphatase RPTPΨ are expressed in restricted regions of the developing central nervous system. Dev. Dyn. 208, 48–61 (1997).
Wallace, M.J., Fladd, C., Batt, J. & Rotin, D. The second catalytic domain of the protein tyrosine phosphatase δ (PTPδ) binds to and inhibits the first catalytic domain of PTPσ. Mol. Cell. Biol. 18, 2608–2616 (1998).
Jacobowitz, D.M. & Abbott, L.C. Chemoarchitectonic Atlas of the Developing Mouse Brain (CRC, New York, 1997).
Henderson, J.T., Javaheri, M., Kopko, S. & Roder, J.C. Reduction of lower motor neuron disease in wobbler mice by N-acetyl-L-cysteine. J. Neurosci. 16, 7574–7582 (1996).
Robertson, A., Day, B., Pollock, M. & Collier, P. The neuropathy of elderly mice. Acta Neuropathol. 86, 163 –171 (1993).
Smorto, M.P. & Basmajian, J.V. Introduction to nerve conduction tests. in Clinical Electroneurography 19– 56 (Williams and Wilkins, Philadelphia, 1979).
Crawley, J.N. & Paylor, R. A proposed test battery and constellation of specific behavioral paradigms to investigate the behavioral phenotypes of transgenic and knockout mice. Horm. Behav. 31, 197–211 (1997).
Rogers, D.C. et al. Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment. Mamm. Gen. 8, 711–713 (1997).
Irwin, S. Comprehensive observational assessment: Ia. Systematic, quantitative procedure for assessing the behavioral and physiologic state of the mouse. Psychopharmacologia 13, 222–257 (1968).
Oliver, J. & Lorenz, M. Neurologic examination. in Handbook of Veterinary Neurological Disorders 19– 51 (W.B. Saunders, Orlando, 1983).
Ferriere, G., Denef J., Rodriguez, J & Guzzetta, F. Morphometric studies of normal sural nerves in children. Muscle Nerve 8, 697–704 (1985).
Ouvrier, R., McLeod, J.G. & Conchin, T. Morphometric studies of sural nerve in childhood. Muscle Nerve 10, 47–53 (1987).
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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DOI: https://doi.org/10.1038/6866
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