Novel mechanism for gonadotropin-releasing hormone neuronal migration involving Gas6/Ark signaling to p38 mitogen-activated protein kinase
Novel mechanism for gonadotropin-releasing hormone neuronal migration involving Gas6/Ark signaling to p38 mitogen-activated protein kinase
复制标题
DOI：
10.1128/mcb.22.2.599-613.2002
复制
发表时间：
2002-01-01
影响因子：
5.3
通讯作者：
Wierman, ME
中科院分区：
文献类型：
--
作者：
Allen, MP;Linseman, DA;Wierman, ME
促性腺激素释放激素（GnRH）是生殖轴的中心调节因子。正常的性成熟依赖于GnRH神经元在发育过程中从嗅板迁移到下丘脑。在此之前，我们发现在来自迁移性而非迁移后GnRH神经元的永生化细胞系中，膜受体粘附相关激酶（方舟）表达受限。此外，方舟和GnRH转录本检测沿着GnRH神经元迁移路线在E13小鼠筛板。在本研究中，我们研究了方舟和它的配体，Gas 6（由生长停滞特异性基因6编码），在GnRH神经元迁移的作用。Gas 6通过方舟受体刺激板状伪足延伸、膜皱褶和永生化NLT GnRH神经元细胞的趋化性。Gas 6/方舟信号促进了Rho家族GT3 Rac的激活，腺病毒介导的显性负性N17 Rac的表达消除了Gas 6/方舟诱导的肌动蛋白细胞骨架重组和GnRH神经元细胞的迁移。此外，p38 MAPK在方舟和Rac的下游被激活，并且用SB 203580或腺病毒显性阴性p38 α抑制p38 MAPK也阻断Gas 6/Ark介导的迁移。最后，在Rac和p38丝裂原活化蛋白激酶（MAPK）的下游，Gas 6/方舟信号促进MAPK活化蛋白激酶2的活化，并诱导HSP 25的磷酸化，HSP 25是一种已知的皮质肌动蛋白重塑调节因子。这些数据是第一个证明迁移信号通路下游的方舟/Axl家族受体，并建议一个以前未确定的作用p38 MAPK在神经元迁移。此外，这些研究支持方舟在调节GnRH神经元迁移的潜在作用。
Gonadotropin-releasing hormone (GnRH) is the central regulator of the reproductive axis. Normal sexual maturation depends on the migration of GnRH neurons from the olfactory placode to the hypothalamus during development. Previously, we showed restricted expression of the membrane receptor adhesion-related kinase (Ark) in immortalized cell lines derived from migratory but not postmigratory GnRH neurons. In addition, Ark and GnRH transcripts were detected along the GnRH neuron migratory route in the E13 mouse cribriform plate. In the present study, we examined the role of Ark and its ligand, Gas6 (encoded by growth arrest-specific gene 6), in GnRH neuron migration. Gas6 stimulated lamellipodial extension, membrane ruffling, and chemotaxis of immortalized NLT GnRH neuronal cells via the Ark receptor. Gas6/Ark signaling promoted activation of the Rho family GTPase Rac, and adenoviral-mediated expression of dominant negative N17Rac abolished Gas6/Ark-induced actin cytoskeletal reorganization and migration of GnRH neuronal cells. In addition, p38 MAPK was activated downstream of Ark and Rac, and inhibition of p38 MAPK with either SB203580 or adenoviral dominant negative p38 alpha also blocked Gas6/Ark-mediated migration. Finally, downstream of Rac and p38 mitogen-activated protein kinase (MAPK), Gas6/Ark signaling promoted activation of MAPK-activated protein kinase 2 and induced phosphorylation of HSP25, a known regulator of cortical actin remodeling. The data are the first to demonstrate a migratory signaling pathway downstream of Ark/Axl family receptors and suggest a previously unidentified role for p38 MAPK in neuronal migration. Furthermore, these studies support a potential role for Ark in the regulation of GnRH neuronal migration.