Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice
Open Access
- 22 August 2011
- journal article
- research article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 208 (9), 1835-1847
- https://doi.org/10.1084/jem.20110571
Abstract
Cerebral cavernous malformations (CCM) are vascular malformations of the central nervous system (CNS) that lead to cerebral hemorrhages. Familial CCM occurs as an autosomal dominant condition caused by loss-of-function mutations in one of the three CCM genes. Constitutive or tissue-specific ablation of any of the Ccm genes in mice previously established the crucial role of Ccm gene expression in endothelial cells for proper angiogenesis. However, embryonic lethality precluded the development of relevant CCM mouse models. Here, we show that endothelial-specific Ccm2 deletion at postnatal day 1 (P1) in mice results in vascular lesions mimicking human CCM lesions. Consistent with CCM1/3 involvement in the same human disease, deletion of Ccm1/3 at P1 in mice results in similar CCM lesions. The lesions are located in the cerebellum and the retina, two organs undergoing intense postnatal angiogenesis. Despite a pan-endothelial Ccm2 deletion, CCM lesions are restricted to the venous bed. Notably, the consequences of Ccm2 loss depend on the developmental timing of Ccm2 ablation. This work provides a highly penetrant and relevant CCM mouse model.This publication has 63 references indexed in Scilit:
- Loss of cerebral cavernous malformation 3 ( Ccm3 ) in neuroglia leads to CCM and vascular pathologyProceedings of the National Academy of Sciences of the United States of America, 2011
- Cerebral cavernous malformations proteins inhibit Rho kinase to stabilize vascular integrityThe Journal of Experimental Medicine, 2010
- β1 Integrin Establishes Endothelial Cell Polarity and Arteriolar Lumen Formation via a Par3-Dependent MechanismDevelopmental Cell, 2010
- A mitotic transcriptional switch in polycystic kidney diseaseNature Medicine, 2009
- Wnt9b signaling regulates planar cell polarity and kidney tubule morphogenesisNature Genetics, 2009
- The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPasesNature Medicine, 2009
- Wnt/β-catenin signaling controls development of the blood–brain barrierThe Journal of cell biology, 2008
- A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1Nature Medicine, 2007
- KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell–cell junctionsThe Journal of cell biology, 2007
- Defective planar cell polarity in polycystic kidney diseaseNature Genetics, 2005