Article abstract
Nature Medicine , 169 - 176 (2009)
Published online: 18 January 2009 | Corrected online: 27 January 2009 | Corrected online: 12 February 2009 | doi:10.1038/nm.1918
There is a Corrigendum (May 2009) associated with this Article.
Regulation of cardiovascular development and integrity by the heart of glass–cerebral cavernous malformation protein pathway
Benjamin Kleaveland1, Xiangjian Zheng1, Jian J Liu2, Yannick Blum3, Jennifer J Tung4, Zhiying Zou1, Shawn M Sweeney1, Mei Chen1, Lili Guo1, Min-min Lu1, Diane Zhou1, Jan Kitajewski4, Markus Affolter3, Mark H Ginsberg2 & Mark L Kahn1
Abstract
Cerebral cavernous malformations (CCMs) are human vascular malformations caused by mutations in three genes of unknown function: KRIT1, CCM2 and PDCD10. Here we show that the heart of glass (HEG1) receptor, which in zebrafish has been linked to ccm gene function, is selectively expressed in endothelial cells. Heg1-/- mice showed defective integrity of the heart, blood vessels and lymphatic vessels. Heg1-/-; Ccm2lacZ/+ and Ccm2lacZ/lacZ mice had more severe cardiovascular defects and died early in development owing to a failure of nascent endothelial cells to associate into patent vessels. This endothelial cell phenotype was shared by zebrafish embryos deficient in heg, krit1 or ccm2 and reproduced in CCM2-deficient human endothelial cells in vitro. Defects in the hearts of zebrafish lacking heg or ccm2, in the aortas of early mouse embryos lacking CCM2 and in the lymphatic vessels of neonatal mice lacking HEG1 were associated with abnormal endothelial cell junctions like those observed in human CCMs. Biochemical and cellular imaging analyses identified a cell-autonomous pathway in which the HEG1 receptor couples to KRIT1 at these cell junctions. This study identifies HEG1-CCM protein signaling as a crucial regulator of heart and vessel formation and integrity.
- Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 421 Curie Blvd., Philadelphia, Pennsylvania 19104, USA.
- Department of Medicine, University of California, San Diego, 9500 Gilman Drive, MC 0726, La Jolla, California 92093-0726, USA.
- Biozentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland.
- Department of Pathology and Department of Obstetrics and Gynecology, Institute of Cancer Genetics and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York 10032, USA.
Correspondence to: Mark L Kahn1 e-mail: markkahn@mail.med.upenn.edu
** In this version of the article initially published, Shawn M. Sweeney was not included in the list of authors. The error has been corrected in the HTML and PDF versions of the article.
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
NEWS AND VIEWS
Research highlightsNature Cell Biology News and Views (01 Mar 2009)
Torturing a blood vesselNature Medicine News and Views (01 Feb 2009)
See all 4 matches for News And ViewsRESEARCH
The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPasesNature Medicine Article (01 Feb 2009)
The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular systemNature Article (11 Nov 2004)
See all 32 matches for Research
