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.
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Acknowledgements
We thank L.-Y. Kung for technical assistance in PCR genotyping; R. Smeyne for discussions; and K. Johnson and M. Davisson for mapping reagents. This work was supported in part by an NIH Cancer Center Support CORE grant, a grant from the NINDS (T.C.), the American Lebanese Syrian Associated Charities (ALSAC), NRSA from NCI (M.S.), NRSA from NINDS (G.D.), the University of Tennessee and the Department of Anatomy and Neurobiology, the Science and Technology Agency of the Japanese Government, and the Ministry of Education, Science and Culture of Japan.
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Sheldon, M., Rice, D., D'Arcangelo, G. et al. Scrambler and yotari disrupt the disabled gene and produce a reeler -like phenotype in mice. Nature 389, 730–733 (1997). https://doi.org/10.1038/39601
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DOI: https://doi.org/10.1038/39601
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