Notch signaling is required for the formation of mesangial cells from a stromal mesenchyme precursor during kidney development
Notch signaling is required for the formation of mesangial cells from a stromal mesenchyme precursor during kidney development
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DOI：
10.1242/dev.100271
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发表时间：
2014-01-15
期刊：
影响因子：
4.6
通讯作者：
Kopan, Raphael
中科院分区：
文献类型：
--
作者：
Boyle, Scott C.;Liu, Zhenyi;Kopan, Raphael
肾小球系膜细胞是特化的周细胞/平滑肌细胞，其包围并限制肾脏肾小球内的血管网络。它们来源于间质间充质，一种不同于肾单位干细胞的祖细胞群。肾小球系膜细胞是否与血管平滑肌细胞（VSMCs）有不同的起源以及控制其特化的途径尚不清楚。在这里，我们表明，Notch信号在基质祖细胞是必不可少的系膜细胞的形成，但平滑肌和间质细胞谱系是不稳定的。RBPjk（所有活性Notch受体的共同DNA结合伴侣）与Foxd 1（tgCre）的缺失导致肾小球动脉瘤和肾衰竭引起的围产期死亡。这种缺陷发生在肾小球发育的早期，因为基质来源的结蛋白阳性细胞不能在形成的肾单位附近合并，因此不能侵入S形体的血管裂隙。这与其中系膜的损失是由于迁移缺陷的其他突变体形成对比，并且表明Notch信号传导的损失导致未能从基质中指定该群体。有趣的是，Pdgfrb阳性的VSMCs不进入血管裂隙，不能挽救系膜缺陷。Notch 1和Notch 2通过γ-分泌酶和RBPjk在这个过程中发挥冗余作用，因为个别突变体在出生时就有系膜细胞。总之，这些数据证明了系膜细胞的独特起源，并证明了Notch受体在肾脏发育过程中系膜细胞特化、增殖或存活中的新的冗余功能。
Mesangial cells are specialized pericyte/smooth muscle cells that surround and constrain the vascular network within the glomerulus of the kidney. They are derived from the stromal mesenchyme, a progenitor population distinct from nephron stem cells. Whether mesangial cells have a distinct origin from vascular smooth muscle cells (VSMCs) and the pathways that govern their specification are unknown. Here we show that Notch signaling in stromal progenitors is essential for mesangial cell formation but is dispensable for the smooth muscle and interstitial cell lineages. Deletion of RBPjk, the common DNA-binding partner of all active Notch receptors, with Foxd1(tgCre) results in glomerular aneurysm and perinatal death from kidney failure. This defect occurs early in glomerular development as stromal-derived, desmin-positive cells fail to coalesce near forming nephrons and thus do not invade the vascular cleft of the S-shaped body. This is in contrast to other mutants in which the loss of the mesangium was due to migration defects, and suggests that loss of Notch signaling results in a failure to specify this population from the stroma. Interestingly, Pdgfrb-positive VSMCs do not enter the vascular cleft and cannot rescue the mesangial deficiency. Notch1 and Notch2 act redundantly through gamma-secretase and RBPjk in this process, as individual mutants have mesangial cells at birth. Together, these data demonstrate a unique origin of mesangial cells and demonstrate a novel, redundant function for Notch receptors in mesangial cell specification, proliferation or survival during kidney development.