Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 99, Issue 23, Pages 15200-15205Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.222362099
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Cerebellar development occurs mainly postnatally and implies cell proliferation and migration. Hepatocyte growth factor (HGF) and Met are involved in mediating these responses in other tissues and are coexpressed in the cerebellum. Here we show that Met is localized in granule cell precursors and that cultures of these cells respond to HGIF with proliferation. To study the role of HGIF and Met in the cerebellum in vivo, we produced a viable hypomorphic Met mutant by knocking in the met locus a point mutation to abrogate the receptor Grb2-binding site. A similar mutant was previously described as perinatal lethal. In this first-generation knock-in the recombinant locus retained the Neo cassette (Met(grb2/grb2neo+)). In the knock-in presented here Neo was Loxed and excised by Cre recombinase, which led to higher tissue levels of Met(grb2) protein, sufficient to rescue viability. In Met(grb2/grb2neo-) mice the size of the cerebellum was reduced and foliation defects were evident, especially in the central and posterior half of the vermis. Proliferation of granule precursors in vivo was 25% lower than in controls. In cultures of mutant granule cells HGF-induced microtubule-associated protein kinase activation was reduced and transient. Behavioral tests indicated a balance impairment in Met(grb2/grb2neo-) mice. Altogether these data indicate that normal cerebellar development and, possibly, function, require HGIF and Met, and that proliferation of granule cells in the cerebellum critically depends on full HGF/Met signaling.
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