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Brain development involves a combination of neuronal proliferation, migration, differentiation, neurite projections and synapse formation, to establish a complex neural network. Defects in these processes can lead to severe developmental abnormalities in children, including neurodegeneration, and formation of brain tumors. SPTBN2, which encodes β-III spectrin, is mutated in spinocerebellar ataxia type 5 (SCA5), a neurodegenerative disorder resulting in uncoordinated gait, limb and eye movements, and slurred speech. Mice deficient in β-III spectrin develop a SCA5 phenotype in an age-dependent manner, including gait abnormality, tremors, cerebellar atrophy, and Purkinje cell loss. Previously, we demonstrated that mice lacking both Crk and CrkL in neurons display significant defects in brain development, including cerebellar hypofoliation, failure of Purkinje cell migration, impaired dendritic development, and disruption of layer formation mediated by the Reelin pathway.

Recently, exome sequencing of a child with a severe global developmental delay, poor growth, and ataxia revealed compound heterozygous mutations in CRK (a truncation mutation: CRK-R88X) and SPTBN2 (a point mutation: SPTBN2-M136V). The siblings carried the same mutation in SPTBN2, but they were asymptomatic. We hypothesize that the interaction between Crk and β-III spectrin is important for brain development and that β-III spectrin lies downstream of Crk in the Reelin signaling pathway.

Three-dimensional molecular modeling indicated that the truncation mutation CRK-R88X renders the Crk protein unstable and inactive. Both β-III spectrin and Crk proteins were detected in mouse embryonic cortical extracts by Western blot analysis. We generated single heterozygous mutant mice for CRK-R88X and SPTBN2-M136V, respectively, and crossed them to generate double heterozygous mice. The double heterozygous mice did not exhibit weight loss or ataxia at 2 months. Hematoxylin and eosin staining of 2-month-old double mutant mouse brains did not show any gross anatomical defects. We plan to carry out immunohistochemistry analysis to determine further details of brain development in these mice. We will also examine motor coordination changes using behavioral test instruments for potential neurodegeneration associated with aging.

Our goal is to determine whether the clinical findings are recapitulated in our mouse models. Results obtained from the mouse models would provide insights into the interaction between Crk and β-III spectrin during brain development and neurodegeneration.


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Interaction between Crk and β-III spectrin during brain development and neurodegeneration


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