Oproescu Ana-Maria, Han Sisu, Schuurmans Carol
Sunnybrook Research Institute, Biological Sciences Platform, Toronto, ON, Canada.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Front Mol Neurosci. 2021 Feb 15;14:642016. doi: 10.3389/fnmol.2021.642016. eCollection 2021.
Historically, the mammalian brain was thought to lack stem cells as no new neurons were found to be made in adulthood. That dogma changed ∼25 years ago with the identification of neural stem cells (NSCs) in the adult rodent forebrain. However, unlike rapidly self-renewing mature tissues (e.g., blood, intestinal crypts, skin), the majority of adult NSCs are quiescent, and those that become 'activated' are restricted to a few neurogenic zones that repopulate specific brain regions. Conversely, embryonic NSCs are actively proliferating and neurogenic. Investigations into the molecular control of the quiescence-to-proliferation-to-differentiation continuum in the embryonic and adult brain have identified proneural genes encoding basic-helix-loop-helix (bHLH) transcription factors (TFs) as critical regulators. These bHLH TFs initiate genetic programs that remove NSCs from quiescence and drive daughter neural progenitor cells (NPCs) to differentiate into specific neural cell subtypes, thereby contributing to the enormous cellular diversity of the adult brain. However, new insights have revealed that proneural gene activities are context-dependent and tightly regulated. Here we review how proneural bHLH TFs are regulated, with a focus on the murine cerebral cortex, drawing parallels where appropriate to other organisms and neural tissues. We discuss upstream regulatory events, post-translational modifications (phosphorylation, ubiquitinylation), protein-protein interactions, epigenetic and metabolic mechanisms that govern bHLH TF expression, stability, localization, and consequent transactivation of downstream target genes. These tight regulatory controls help to explain paradoxical findings of changes to bHLH activity in different cellular contexts.
从历史上看，哺乳动物的大脑被认为缺乏干细胞，因为在成年期未发现有新的神经元生成。大约25年前，随着成年啮齿动物前脑中神经干细胞（NSCs）的发现，这一教条发生了改变。然而，与快速自我更新的成熟组织（如血液、肠隐窝、皮肤）不同，大多数成年神经干细胞处于静止状态，而那些“被激活”的神经干细胞仅限于少数几个神经发生区，这些区域会重新填充特定的脑区。相反，胚胎神经干细胞则在积极增殖并具有神经发生能力。对胚胎和成年大脑中静止-增殖-分化连续过程的分子控制的研究已经确定，编码碱性螺旋-环-螺旋（bHLH）转录因子（TFs）的神经源性基因是关键调节因子。这些bHLH转录因子启动遗传程序，使神经干细胞从静止状态中脱离出来，并驱动子代神经祖细胞（NPCs）分化为特定的神经细胞亚型，从而促成成年大脑中巨大的细胞多样性。然而，新的见解表明，神经源性基因的活动是依赖于环境的，并且受到严格调控。在这里，我们回顾神经源性bHLH转录因子是如何被调控的，重点是小鼠大脑皮层，并在适当的地方与其他生物体和神经组织进行比较。我们讨论了上游调控事件、翻译后修饰（磷酸化、泛素化）、蛋白质-蛋白质相互作用、表观遗传和代谢机制，这些机制控制着bHLH转录因子的表达、稳定性、定位以及下游靶基因的后续反式激活。这些严格的调控有助于解释在不同细胞环境中bHLH活性变化的矛盾发现。
