Scrambler and yotari disrupt the disabled gene and produce a reeler -like phenotype in mice

Michael Sheldon, Dennis S. Rice, Gabriella D'Arcangelo, Hiroyuki Yoneshima, Kazunori Nakajima, Katsuhiko Mikoshiba, Brian W. Howell, Jonathan A. Cooper, Dan Goldowitz and Tom Curran ()
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Michael Sheldon: St Jude Children's Research Hospital
Dennis S. Rice: St Jude Children's Research Hospital
Gabriella D'Arcangelo: St Jude Children's Research Hospital
Hiroyuki Yoneshima: Institute of Medical Science, University of Tokyo
Kazunori Nakajima: Molecular Neurobiology Laboratory, Tsukuba Life Science Center, The Institute of Physical and Chemical Research (RIKEN)
Katsuhiko Mikoshiba: Institute of Medical Science, University of Tokyo
Brian W. Howell: Fred Hutchinson Cancer Research Center Seattle
Jonathan A. Cooper: Fred Hutchinson Cancer Research Center Seattle
Dan Goldowitz: University of Tennessee College of Medicine
Tom Curran: St Jude Children's Research Hospital

Nature, 1997, vol. 389, issue 6652, 730-733

Abstract: Abstract Formation of the mammalian brain requires choreographed migration of neurons to generate highly ordered laminar structures such as those in the cortices of the forebrain and the cerebellum. These processes are severely disrupted by mutations in reelin1 which cause widespread misplacement of neurons and associated ataxia in reeler mice2,3. Reelin is a large extracellular protein secreted by pioneer neurons that coordinates cell positioning during neurodevelopment1,4,5,6,7,8. Two new autosomal recessive mouse mutations, scrambler9 and yotari10 have been described that exhibit a phenotype identical to reeler9,10,11. Here we report that scrambler and yotari arise from mutations in mdab1 (ref. 12), a mouse gene related to the Drosophila gene disabled ( dab )13. Both scrambler and yotari mice express mutated forms of mdab1 messenger RNA and little or no mDab1 protein. mDab1 is a phosphoprotein that appears to function as an intracellular adaptor in protein kinase pathways. Expression analysis indicates that mdab1 is expressed in neuronal populations exposed to Reelin. The similar phenotypes of reeler, scrambler, yotari and mdab1 null mice14 indicate that Reelin and mDab1 function as signalling molecules that regulate cell positioning in the developing brain.

Date: 1997
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DOI: 10.1038/39601

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