Zhang X M, Yang X J
Department of Ophthalmology, Jules Stein Eye Institute, Molecular Biology Institute, UCLA School of Medicine, Los Angeles, CA 90095, USA.
Development. 2001 Mar;128(6):943-57. doi: 10.1242/dev.128.6.943.
Previous work has shown that production of retinal ganglion cells is in part regulated by inhibitory factors secreted by ganglion cell themselves; however, the identities of these molecules are not known. Recent studies have demonstrated that the signaling molecule Sonic hedgehog (Shh) secreted by differentiated retinal ganglion cells is required to promote the progression of ganglion cell differentiation wave front and to induce its own expression. We present evidence that Shh signals play a role to negatively regulate ganglion cell genesis behind the differentiation wave front. Higher levels of Shh expression are detected behind the wave front as ganglion cells accumulate, while the Patched 1 receptor of Shh is expressed in adjacent retinal progenitor cells. Retroviral-mediated overexpression of Shh results in reduced ganglion cell proportions in vivo and in vitro. Conversely, inhibiting endogenous Shh activity by anti-Shh antibodies leads to an increased production of ganglion cells. Shh signals modulate ganglion cell production within the normal period of ganglion cell genesis in vitro without significantly affecting cell proliferation or cell death. Moreover, Shh signaling affects progenitor cell specification towards the ganglion cell fate during or soon after their last mitotic cycle. Thus, Shh derived from differentiated ganglion cells serves as a negative regulator behind the differentiation wave front to control ganglion cell genesis from the competent progenitor pool. Based on these results and other recent findings, we propose that Shh signals secreted by early-differentiated retinal neurons play dual roles at distinct concentration thresholds to orchestrate the progression of retinal neurogenic wave and the emergence of new neurons.
先前的研究表明，视网膜神经节细胞的生成部分受神经节细胞自身分泌的抑制因子调控；然而，这些分子的具体身份尚不清楚。最近的研究表明，分化的视网膜神经节细胞分泌的信号分子音猬因子（Shh）对于促进神经节细胞分化波前的进展以及诱导其自身表达是必需的。我们提供的证据表明，Shh信号在分化波前的后方对神经节细胞的发生起负调控作用。随着神经节细胞的积累，在波前的后方检测到更高水平的Shh表达，而Shh的patched 1受体则在相邻的视网膜祖细胞中表达。逆转录病毒介导的Shh过表达导致体内和体外神经节细胞比例降低。相反，用抗Shh抗体抑制内源性Shh活性会导致神经节细胞生成增加。Shh信号在体外神经节细胞正常生成期内调节神经节细胞的产生，而不会显著影响细胞增殖或细胞死亡。此外，Shh信号在祖细胞最后一个有丝分裂周期期间或之后影响其向神经节细胞命运的特化。因此，来自分化神经节细胞的Shh作为分化波前后方的负调控因子，从有能力的祖细胞池中控制神经节细胞的生成。基于这些结果和其他近期发现，我们提出，早期分化的视网膜神经元分泌的Shh信号在不同的浓度阈值下起双重作用，以协调视网膜神经源性波的进展和新神经元的出现。
