Regulation of cardiovascular development and integrity by the heart of glass-cerebral cavernous malformation protein pathway.
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(-/-); Ccm2(lacZ/+) and Ccm2(lacZ/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.
Kleaveland
Benjamin
B
Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 421 Curie Blvd., Philadelphia, Pennsylvania 19104, USA.
Zheng
Xiangjian
X
Liu
Jian J
JJ
Blum
Yannick
Y
Tung
Jennifer J
JJ
Zou
Zhiying
Z
Sweeney
Shawn M
SM
Chen
Mei
M
Guo
Lili
L
Lu
Min-min
MM
Zhou
Diane
D
Kitajewski
Jan
J
Affolter
Markus
M
Ginsberg
Mark H
MH
Kahn
Mark L
ML
D000818:Animals; D002319:Cardiovascular System / Q000196:embryology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020786:Hemangioma, Cavernous, Central Nervous System / Q000503:physiopathology*; D006470:Hemorrhage / Q000235:genetics; D006801:Humans; D000075927:KRIT1 Protein; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
C502544:CCM2 protein, human; D002352:Carrier Proteins; D000075927:KRIT1 Protein; C491535:Krit1 protein, mouse; D008562:Membrane Glycoproteins; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D029961:Zebrafish Proteins; C482644:heg1 protein, zebrafish