Institute of Molecular Medicine and Genetics and Department of Neurology, Medical College of Georgia, Augusta, GA 30912, USA.
Dev Cell. 2010 Jul 20;19(1):90-102. doi: 10.1016/j.devcel.2010.06.016.
Neogenin has been identified as a receptor for the neuronal axon guidance cues netrins and RGMs (repulsive guidance molecules). Here we provide evidence for neogenin in regulating endochondral bone development and BMP (bone morphogenetic protein) signaling. Neogenin-deficient mice were impaired in digit/limb development and endochondral ossification. BMP2 induction of Smad1/5/8 phosphorylation and Runx2 expression, but not noncanonical p38 MAPK activation, was reduced in chondrocytes from neogenin mutant mice. BMP receptor association with membrane microdomains, which is necessary for BMP signaling to Smad, but not p38 MAPK, was diminished in neogenin-deficient chondrocytes. Furthermore, RGMs appear to mediate neogenin interaction with BMP receptors in chondrocytes. Taken together, our results indicate that neogenin promotes chondrogenesis in vitro and in vivo, revealing an unexpected mechanism underlying neogenin regulation of BMP signaling.
Neogenin 已被鉴定为神经元轴突导向线索 netrins 和 RGMs（排斥性导向分子）的受体。在这里，我们提供了 Neogenin 在调节软骨内骨发育和 BMP（骨形态发生蛋白）信号转导中的证据。Neogenin 缺陷小鼠在指/趾发育和软骨内骨化中受损。在 Neogenin 突变型小鼠的软骨细胞中，BMP2 诱导的 Smad1/5/8 磷酸化和 Runx2 表达减少，但非典型 p38 MAPK 激活减少。BMP 受体与膜微区的关联对于 BMP 信号转导至 Smad，但不是 p38 MAPK，在 Neogenin 缺陷型软骨细胞中减少。此外，RGMs 似乎介导 Neogenin 与软骨细胞中 BMP 受体的相互作用。总之，我们的结果表明 Neogenin 促进体外和体内的软骨生成，揭示了 Neogenin 调节 BMP 信号转导的一种意外机制。
