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Neuronal expression of the Ccm2 gene in a new mouse model of cerebral cavernous malformations

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Abstract

Cerebral cavernous malformations are vascular defects of the central nervous system consisting of clusters of dilated vessels that are subject to frequent hemorrhaging. The genes mutated in three forms of autosomal dominant cerebral cavernous malformations have been cloned, but it remains unclear which cell type is ultimately responsible for the lesion. In this article we describe mice with a gene trap insertion in the Ccm2 gene. Consistent with the human phenotype, heterozygous animals develop cerebral vascular malformations, although penetrance is low. β-galactosidase activity in heterozygous brain and in situ hybridization in wild-type brain revealed Ccm2 expression in neurons and choroid plexus but not in vascular endothelium of small vessels in the brain. The expression pattern of Ccm2 is similar to that of the Ccm1 gene and its interacting protein ICAP1 (Itgb1bp1). These data suggest that cerebral cavernous malformations arise as a result of defects in the neural parenchyma surrounding the vascular endothelial cells in the brain.

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Acknowledgments

This work was supported by NIH grant NS-43543 and American Heart Association Bugher Foundation Award for the Investigation of Stroke 0070028 N to DAM. Cheryl Bock and the Duke University Transgenic Mouse Facility cultured the RRG051 embryonic stem cells and generated the chimeric mice. The authors thank Hai Yan Lin, Momoka Matsunami, Quiyi Chi, and Natasha Thorne for technical assistance, and Christopher Clayton for help with mouse colony maintenance.

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Authors and Affiliations

  1. Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, 27710, USA

    Nicholas W. Plummer, Teresa L. Squire, Sudha Srinivasan, Elizabeth Huang, Jon S. Zawistowski, Hiroaki Matsunami & Douglas A. Marchuk

  2. Department of Pathology, Duke University Medical Center, Durham, North Carolina, 27710, USA

    Laura P. Hale

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  1. Nicholas W. Plummer
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  2. Teresa L. Squire
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  3. Sudha Srinivasan
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  4. Elizabeth Huang
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  5. Jon S. Zawistowski
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  6. Hiroaki Matsunami
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  7. Laura P. Hale
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  8. Douglas A. Marchuk
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Correspondence to Douglas A. Marchuk.

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Nicholas W. Plummer, Teresa L. Squire and Sudha Srinivasan contributed equally to this work.

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Plummer, N.W., Squire, T.L., Srinivasan, S. et al. Neuronal expression of the Ccm2 gene in a new mouse model of cerebral cavernous malformations. Mamm Genome 17, 119–128 (2006). https://doi.org/10.1007/s00335-005-0098-8

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  • DOI: https://doi.org/10.1007/s00335-005-0098-8

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