Crim1KST264/KST264 mice implicate Crim1 in the regulation of vascular endothelial growth factor-A activity during glomerular vascular development.
Crim1, a transmembrane cysteine-rich repeat-containing protein that is related to chordin, plays a role in the tethering of growth factors at the cell surface. Crim1 is expressed in the developing kidney; in parietal cells, podocytes, and mesangial cells of the glomerulus; and in pericytes that surround the arterial vasculature. A gene-trap mouse line with an insertion in the Crim1 gene (Crim1(KST264/KST264)) displayed perinatal lethality with defects in multiple organ systems. This study further analyzed the defects that are present within the kidneys of these mice. Crim1(KST264/KST264) mice displayed abnormal glomerular development, illustrated by enlarged capillary loops, podocyte effacement, and mesangiolysis. When outbred, homozygotes that reached birth displayed podocyte and glomerular endothelial cell defects and marked albuminuria. The podocytic co-expression of Crim1 with vascular endothelial growth factor-A (VEGF-A) suggested a role for Crim1 in the regulation of VEGF-A action. Crim1 and VEGF-A were shown to interact directly, providing evidence that cysteine-rich repeat-containing proteins can bind to non-TGF-beta superfamily ligands. Crim1(KST264/KST264) mice display a mislocalization of VEGF-A within the developing glomerulus, as assessed by immunogold electron microscopy and increased activation of VEGF receptor 2 (Flk1) in the glomerular endothelial cells, suggesting that Crim1 regulates the delivery of VEGF-A by the podocytes to the endothelial cells. This is the first in vivo demonstration of regulation of VEGF-A delivery and supports the hypothesis that Crim1 functions to regulate the release of growth factors from the cell of synthesis.
Wilkinson
Lorine
L
Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia 4072.
Gilbert
Thierry
T
Kinna
Genevieve
G
Ruta
Leah-Anne
LA
Pennisi
David
D
Kett
Michelle
M
Little
Melissa H
MH
D000367:Age Factors; D000419:Albuminuria / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D021461:Animals, Outbred Strains; D052004:Bone Morphogenetic Protein Receptors / Q000235:genetics* / Q000378:metabolism*; D019556:COS Cells; D002196:Capillaries / Q000196:embryology / Q000378:metabolism; D002522:Chlorocebus aethiops; D003553:Cystine / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D005919:Glomerular Filtration Rate; D007678:Kidney Glomerulus / Q000098:blood supply* / Q000196:embryology* / Q000648:ultrastructure; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016253:Microscopy, Immunoelectron; D050199:Podocytes / Q000378:metabolism / Q000648:ultrastructure; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
C518411:Crim1 protein, mouse; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D003553:Cystine; D040301:Vascular Endothelial Growth Factor Receptor-2; D052004:Bone Morphogenetic Protein Receptors