Crim1KST264/KST264 mice implicate Crim1 in the regulation of vascular endothelial growth factor-A activity during glomerular vascular development
Crim1KST264/KST264 mice implicate Crim1 in the regulation of vascular endothelial growth factor-A activity during glomerular vascular development
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DOI：
10.1681/asn.2006091012
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发表时间：
2007-06-01
影响因子：
13.6
通讯作者：
Little, Melissa H.
中科院分区：
文献类型：
--
作者：
Wilkinson, Lorine;Gilbert, Thierry;Little, Melissa H.
CRIM1是一种与Chordin相关的跨膜富含半胱氨酸重复序列的蛋白，在细胞表面生长因子的捆绑中发挥作用。CRIM1在发育中的肾脏、肾小球的壁细胞、足细胞和系膜细胞以及动脉血管周围的周细胞中表达。插入Crim1基因的基因陷阱小鼠品系(Crim1(KST264/KST264))显示出围产期死亡，并伴有多个器官系统的缺陷。这项研究进一步分析了这些小鼠肾脏中存在的缺陷。CRIM1(KST264/KST264)小鼠肾小球发育异常，表现为毛细血管环增大、足细胞减少和系膜溶解。当异种繁殖时，出生的纯合子表现为足细胞和肾小球内皮细胞缺陷，并出现明显的蛋白尿。Crim1与血管内皮生长因子-A(VEGF-A)的足细胞共表达提示了Crim1在调节血管内皮生长因子-A的作用中的作用。CRIM1和VEGF-A被证明是直接相互作用的，这提供了富含半胱氨酸重复序列的蛋白可以与非转化生长因子-β超家族配体结合的证据。免疫金电镜示CRIM1(KST264/KST264)小鼠肾小球内血管内皮生长因子-A定位错误，肾小球内皮细胞中血管内皮生长因子受体2(Flk1)活性增强，提示CRIM1调控足细胞向内皮细胞输送血管内皮生长因子-A。这是第一次在体内证明了调节血管内皮生长因子-A的传递，并支持了Crim1功能调节合成细胞释放生长因子的假说。
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.