Angiogenic sprouting into neural tissue requires Gpr124, an orphan G protein-coupled receptor
Angiogenic sprouting into neural tissue requires Gpr124, an orphan G protein-coupled receptor
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DOI：
10.1073/pnas.1019761108
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发表时间：
2011-02-15
影响因子：
11.1
通讯作者：
Gale, Nicholas W.
中科院分区：
文献类型：
--
作者：
Anderson, Keith D.;Pan, Li;Gale, Nicholas W.
CNS的脉管系统在结构上和功能上不同于其他器官系统的脉管系统，并且特别容易发生发育异常和出血。虽然其他胚胎组织经历初级血管化，但发育中的神经系统是独特的，因为它是通过从周围的神经周围丛萌发血管生成而次级血管化的。这种出芽血管生成需要TGF-β和Wnt途径，因为这些途径的消融导致异常出芽和出血。我们已经从基因上删除了Gpr 124，它是长N-末端B G蛋白偶联受体大家族的一员，其中很少有成员在哺乳动物中鉴定出配体或明确的生物学功能。我们表明，在发展中的中枢神经系统，Gpr 124是专门在血管系统中表达，是绝对必要的适当的血管生成发芽到发展中的神经管。缺乏Gpr 124的胚胎表现出血管缺陷，其特征在于延迟的血管穿透、CNS内病理性肾小球样簇的形成和出血。此外，它们显示出腭和肺发育的缺陷，这两个过程中TGF-β和/或Wnt途径也起着重要作用。我们还表明，TGF-β刺激Gpr 124的表达，和消融Gpr 124的结果在扰动TGF-β途径激活，提示Gpr 124在调节TGF-β信号转导的作用。这些结果代表了一个独特的功能，在哺乳动物系统中的一个长的N-末端组B型G蛋白偶联受体。
The vasculature of the CNS is structurally and functionally distinct from that of other organ systems and is particularly prone to developmental abnormalities and hemorrhage. Although other embryonic tissues undergo primary vascularization, the developing nervous system is unique in that it is secondarily vascularized by sprouting angiogenesis from a surrounding perineural plexus. This sprouting angiogenesis requires the TGF-beta and Wnt pathways because ablation of these pathways results in aberrant sprouting and hemorrhage. We have genetically deleted Gpr124, a member of the large family of long N-terminal group B G protein-coupled receptors, few members of which have identified ligands or well-defined biologic functions in mammals. We show that, in the developing CNS, Gpr124 is specifically expressed in the vasculature and is absolutely required for proper angiogenic sprouting into the developing neural tube. Embryos lacking Gpr124 exhibit vascular defects characterized by delayed vascular penetration, formation of pathological glomeruloid tufts within the CNS, and hemorrhage. In addition, they display defects in palate and lung development, two processes in which TGF-beta and/or Wnt pathways also play important roles. We also show that TGF-beta stimulates Gpr124 expression, and ablation of Gpr124 results in perturbed TGF-beta pathway activation, suggesting roles for Gpr124 in modulating TGF-beta signaling. These results represent a unique function attributed to a long N-terminal group B-type G protein-coupled receptor in a mammalian system.