KRIT1/cerebral cavernous malformation 1 protein localizes to vascular endothelium, astrocytes, and pyramidal cells of the adult human cerebral cortex.
OBJECTIVE
Mutations in KRIT1 cause familial cerebral cavernous malformation, an autosomal dominant disorder affecting primarily the central nervous system vasculature. Although recent studies have suggested that Krev-1 interaction trapped 1 (KRIT1) is a microtubule-associated protein that interacts with integrin cytoplasmic domain-associated protein-1alpha, the function of KRIT1 remains elusive.


METHODS
We used Western blotting and immunohistochemistry with specific KRIT1 polyclonal antibodies to investigate KRIT1 protein expression in diverse cerebral and extracerebral tissues.


RESULTS
Immunostaining demonstrates that although KRIT1 is expressed in a broad variety of human organs, it localizes to the vascular endothelium of each, specifically to capillaries and arterioles. KRIT1 antibody fails to stain fenestrated capillaries in the kidney, the liver, or the red pulp of the spleen, where endothelial cells do not to adhere to one another. In contrast, intense staining is observed in the thymus and the white pulp of the spleen, where specialized blood-organ barriers are formed. Other cell types, including various epithelia, cardiac myocytes, and hepatocytes, also stain with KRIT1.


CONCLUSIONS
Although KRIT1 expression is seen in every endothelium studied, cerebral cavernous malformation lesions are seen almost exclusively in the central nervous system, suggesting that additional cell type(s) contribute to the pathophysiology of cerebral cavernous malformations. Here, we demonstrate that KRIT1 is also present in cells and structures integral to the cerebral angiogenesis and formation of the blood-brain barrier, namely, endothelial cells and astrocytic foot processes, as well as pyramidal neurons in the cerebral cortex.
Guzeloglu-Kayisli
Ozlem
O
Neurovascular Surgery Program, Department of Neurosurgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
Amankulor
Nduka M
NM
Voorhees
Jennifer
J
Luleci
Guven
G
Lifton
Richard P
RP
Gunel
Murat
M
D000328:Adult; D001253:Astrocytes / Q000473:pathology; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D002540:Cerebral Cortex / Q000473:pathology; D002869:Chromosome Aberrations; D004730:Endothelium, Vascular / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D005799:Genes, Dominant / Q000235:genetics*; D006392:Hemangioma, Cavernous / Q000235:genetics / Q000473:pathology; D020786:Hemangioma, Cavernous, Central Nervous System / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D006801:Humans; D007124:Immunoenzyme Techniques; D000075927:KRIT1 Protein; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D017966:Pyramidal Cells / Q000473:pathology
D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins