Nature Genetics
21, 334 - 338 (1999)
doi:10.1038/6866
Neuronal defects and posterior pituitary hypoplasia in mice lacking the
receptor tyrosine phosphatase PTP M.J. Wallace1, 5, 4, J. Batt1, 5, 4, C.A. Fladd1, 5, 4, J.T. Henderson2, W. Skarnes3
& D. Rotin1, 41
The Hospital for Sick Children, Programmes in Cell
and Lung Biology, 555 University Avenue, Toronto
, Ontario, M5G 1X8; 2
Samuel Lunenfeld Research Institute, Mt Sinai Hospital
, 600 University Avenue, Toronto,
Canada.
3
University of California at Berkeley, Department of
Molecular and Cell Biology, 589 Life Science Addition,
Berkeley, California 94720-3200, USA.
4
Biochemistry Department, University of Toronto,
Toronto, Canada. 5
These authors contributed equally to this work.
Correspondence should be addressed to D. Rotin drotin@sickkids.on.caThe LAR-family protein tyrosine phosphatase  (PTP, 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 PTP
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
PTP has a role in neuronal and epithelial development in mice.
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