Department of Neuroscience, Karolinska Institute, S-171 77 Stockholm, Sweden.
J Cell Sci. 2011 Aug 15;124(Pt 16):2797-805. doi: 10.1242/jcs.083717.
GDNF (glial cell line-derived neurotrophic factor) promotes the differentiation and migration of GABAergic neuronal precursors of the medial ganglionic eminence (MGE). These functions are dependent on the GPI-anchored receptor GFRα1, but independent of its two known transmembrane receptor partners RET and NCAM. Here we show that soluble GFRα1 is also able to promote differentiation and migration of GABAergic MGE neurons. These activities require endogenous production of GDNF. Although GDNF responsiveness is abolished in Gfra1(-/-) neurons, it can be restored upon addition of soluble GFRα1, a result that is only compatible with the existence of a previously unknown transmembrane signaling partner for the GDNF-GFRα1 complex in GABAergic neurons. The roles of two candidate transmembrane receptors previously implicated in GABAergic interneuron development--MET, a receptor for hepatocyte growth factor (HGF), and ErbB4, the neuregulin receptor--were examined. GDNF did not induce the activation of either receptor, nor did inhibition of MET or ErbB4 impair GDNF activity in GABAergic MGE neurons. Unexpectedly, however, inhibition of MET or HGF per se promoted neuronal differentiation and migration and enhanced the activity of GDNF on MGE neurons. These effects were dependent on endogenous GDNF and GFRα1, suggesting that MET signaling negatively regulates GDNF activity in the MGE. In agreement with this, Met mutant MGE neurons showed enhanced responses to GDNF and inhibition of MET or HGF increased Gfra1 mRNA expression in MGE cells. In vivo, expression of MET and GFRα1 overlapped in the MGE, and a loss-of-function mutation in Met increased Gfra1 expression in this region. Together, these observations demonstrate the existence of a novel transmembrane receptor partner for the GDNF-GFRα1 complex and uncover an unexpected interplay between GDNF-GFRα1 and HGF-MET signaling in the early diversification of cortical GABAergic interneuron subtypes.
胶质细胞源性神经营养因子（GDNF）促进内侧神经节隆起（MGE）的 GABA 能神经元前体的分化和迁移。这些功能依赖于 GPI 锚定受体 GFRα1，但不依赖于其两个已知的跨膜受体伙伴 RET 和 NCAM。在这里，我们表明可溶性 GFRα1 也能够促进 GABA 能 MGE 神经元的分化和迁移。这些活动需要内源性 GDNF 的产生。尽管 Gfra1(-/-)神经元中的 GDNF 反应性被消除，但可以通过添加可溶性 GFRα1 来恢复，这一结果仅与 GABA 能神经元中 GDNF-GFRα1 复合物的先前未知的跨膜信号伴侣的存在相一致。先前涉及 GABA 能中间神经元发育的两种候选跨膜受体——肝细胞生长因子（HGF）的受体 MET 和神经调节蛋白受体 ErbB4 的作用进行了研究。GDNF 没有诱导这两种受体的激活，也没有抑制 MET 或 ErbB4 损害 GABA 能 MGE 神经元中的 GDNF 活性。然而，出人意料的是，MET 或 HGF 的抑制本身促进了神经元的分化和迁移，并增强了 GDNF 对 MGE 神经元的活性。这些作用依赖于内源性 GDNF 和 GFRα1，表明 MET 信号在 MGE 中负调节 GDNF 活性。与这一结果一致的是，Met 突变的 MGE 神经元对 GDNF 的反应增强，并且抑制 MET 或 HGF 增加了 MGE 细胞中 Gfra1 mRNA 的表达。在体内，MET 和 GFRα1 的表达在 MGE 中重叠，并且 Met 的功能丧失突变增加了该区域中的 Gfra1 表达。总之，这些观察结果表明 GDNF-GFRα1 复合物存在新的跨膜受体伙伴，并揭示了 GDNF-GFRα1 和 HGF-MET 信号之间在皮质 GABA 能中间神经元亚型早期多样化中的意外相互作用。
