CCM2 expression parallels that of CCM1.
OBJECTIVE
Mutations in CCM2 (MGC4607 or malcavernin) cause familial cerebral cavernous malformation (CCM), an autosomal dominant neurovascular disease. Both the function of this molecule and the pathogenesis of the disease remain elusive.


METHODS
We analyzed the mRNA expression of Ccm1 and Ccm2 in the embryonic and postnatal mouse brain by in situ hybridization. Subsequently, we generated CCM2-specific polyclonal antibodies and tested their specificity using transient transfection experiments in various cell lines. We then investigated CCM2 protein expression in cerebral and extracerebral tissues by Western blot analysis as well as immunohistochemistry and compared these results with CCM1 (KRIT1) protein expression.


RESULTS
In situ analysis shows similar temporal and spatial expression patterns for Ccm1 and Ccm2, although Ccm1 expression appears more widespread. Immunohistochemical analysis shows that CCM2 is expressed in various human organs, most noticeably in the arterial vascular endothelium. As is the case with CCM1, CCM2 is not expressed in other vascular wall elements such as smooth muscle cells or the venous circulation. Within cerebral tissue, it is also expressed in pyramidal neurons, astrocytes, and their foot processes. In extracerebral tissues, CCM2 is present in various epithelial cells necessary for blood-organ barrier formation.


CONCLUSIONS
CCM1 and CCM2 have similar expression patterns during development and postnatally thereafter. Given the fact that the disease phenotypes caused by mutations in either gene are clinically and pathologically indistinguishable, the significant overlap in expression pattern supports the hypothesis that both molecules are involved in the same pathway important for central nervous system vascular development.
Seker
Askin
A
Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA.
Pricola
Katie L
KL
Guclu
Bulent
B
Ozturk
Ali K
AK
Louvi
Angeliki
A
Gunel
Murat
M
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000196:embryology* / Q000473:pathology; D019556:COS Cells; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D002478:Cells, Cultured; D002490:Central Nervous System / Q000473:pathology; D002540:Cerebral Cortex / Q000473:pathology; D002522:Chlorocebus aethiops; D004730:Endothelium, Vascular / Q000166:cytology / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D000075927:KRIT1 Protein; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D009130:Muscle, Smooth / Q000473:pathology; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D020798:Two-Hybrid System Techniques; D014471:Umbilical Veins / Q000166:cytology
C502544:CCM2 protein, human; D002352:Carrier Proteins; D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; C491535:Krit1 protein, mouse; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger