Sohur U Shivraj, Arlotta Paola, Macklis Jeffrey D
Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University Cambridge, MA, USA.
Front Neurosci. 2012 Feb 6;6:12. doi: 10.3389/fnins.2012.00012. eCollection 2012.
Whether induction of low-level neurogenesis in normally non-neurogenic regions of the adult brain mimics aspects of developmental neurogenesis is currently unknown. Previously, we and others identified that biophysically induced, neuron subtype-specific apoptosis in mouse neocortex results in induction of neurogenesis of limited numbers of subtype-appropriate projection neurons with axonal projections to either thalamus or spinal cord, depending on the neuron subtype activated to undergo targeted apoptosis. Here, we test the hypothesis that developmental genes from embryonic corticogenesis are re-activated, and that some of these genes might underlie induction of low-level adult neocortical neurogenesis. We directly investigated this hypothesis via microarray analysis of microdissected regions of young adult mouse neocortex undergoing biophysically activated targeted apoptosis of neocortical callosal projection neurons. We compared the microarray results identifying differentially expressed genes with public databases of embryonic developmental genes. We find that, following activation of subtype-specific neuronal apoptosis, three distinct sets of normal developmental genes are selectively re-expressed in neocortical regions of induced neurogenesis in young adult mice: (1) genes expressed by subsets of progenitors and immature neurons in the developing ventricular and/or subventricular zones; (2) genes normally expressed by developmental radial glial progenitors; and (3) genes involved in synaptogenesis. Together with previous results, the data indicate that at least some developmental molecular controls over embryonic neurogenesis can be re-activated in the setting of induction of neurogenesis in the young adult neocortex, and suggest that some of these activate and initiate adult neuronal differentiation from endogenous progenitor populations. Understanding molecular mechanisms contributing to induced adult neurogenesis might enable directed CNS repair.
目前尚不清楚在成年大脑正常非神经发生区域诱导低水平神经发生是否模拟了发育性神经发生的某些方面。此前，我们和其他人发现，在小鼠新皮层中生物物理诱导的神经元亚型特异性凋亡会导致有限数量的亚型合适的投射神经元发生神经发生，这些神经元根据被激活进行靶向凋亡的神经元亚型，其轴突投射到丘脑或脊髓。在这里，我们测试了一个假设，即胚胎皮质发生过程中的发育基因被重新激活，并且其中一些基因可能是成年新皮层低水平神经发生诱导的基础。我们通过对年轻成年小鼠新皮层进行生物物理激活的胼胝体投射神经元靶向凋亡的显微切割区域进行微阵列分析，直接研究了这个假设。我们将鉴定出差异表达基因的微阵列结果与胚胎发育基因的公共数据库进行了比较。我们发现，在亚型特异性神经元凋亡激活后，三组不同的正常发育基因在年轻成年小鼠诱导神经发生的新皮层区域中被选择性地重新表达：（1）在发育中的脑室和/或室下区由祖细胞和未成熟神经元亚群表达的基因；（2）通常由发育中的放射状胶质祖细胞表达的基因；（3）参与突触形成的基因。结合先前的结果，这些数据表明，在年轻成年新皮层诱导神经发生的情况下，至少一些对胚胎神经发生的发育分子控制可以被重新激活，并表明其中一些激活并启动了内源性祖细胞群体的成年神经元分化。了解促成诱导性成年神经发生的分子机制可能有助于定向中枢神经系统修复。
