Molecular control of self-renewal and neurogenic characteristics of cortical progenitors

大脑皮层在人类的许多高级功能中起着关键作用，因此大脑皮层的畸形或损伤极大地影响了我们的健康。皮层是一个只有很少成体干细胞的组织，因此产生新神经元的能力有限。破译控制皮层祖细胞自我更新潜能的机制将有助于揭示神经发育障碍的原因，也可能有助于制定修复受损和/或老化皮层的策略。我在这个提议中的目的是研究命运转换机制，将自我更新的祖细胞转变为能够在大脑皮层中产生神经元的祖细胞。早期皮层祖细胞具有自我更新能力，并扩大了祖细胞的数量。随后它们分化成神经祖细胞，经过有限的细胞分裂产生神经元。换句话说，皮层祖细胞在早期皮质发生过程中，其特征发生了根本性的变化：从自我更新祖细胞到自我更新能力有限但能产生神经元的神经源性祖细胞。但是，自我更新和神经源性祖细胞的命运是如何决定的，以及如何调节过渡过程仍然是一个重要但尚未解决的问题。之前我已经发现Fgf10，一种成纤维细胞生长调节自我更新到神经源性祖细胞的分化。基于我最初的发现，我的目标是确定决定自我更新的命运的新因素，神经源性祖细胞及其转变。确定控制神经祖细胞更新或分化决定的潜在机制是非常重要的，至少有两个原因。首先，平衡神经祖细胞的自我更新增殖和分化是保证神经系统正常生长的重要发育机制。祖细胞自我更新受损会导致大脑发育不成熟和减少，而不受控制的过度增殖通常会导致过大的大脑和/或癌症。其次，干细胞/祖细胞的使用为开发修复受损神经系统的新策略提供了巨大的潜力，这些受损神经系统缺乏自然再生能力。我坚信这里提出的研究将提供新的发现来解释皮层祖细胞的基本特征：自我更新或神经发生能力。这项研究将为皮质祖细胞的遗传程序提供见解，该程序决定了它们的自我更新潜力和神经源性能力。由于缺乏神经祖细胞，成人皮层几乎没有神经发生的潜力，发展再生医学方法对于修复各种机械损伤、缺血或神经退行性疾病损伤的皮层至关重要。识别和描述皮层祖细胞分化的关键因素不仅将揭示神经祖细胞分化的基本机制，而且可能为我们提供遗传工具或帮助发现药物，使体内分化的细胞（不再能够再生神经元）直接重编程为神经源性或自我更新的祖细胞。在接下来的项目中，我将测试我的候选基因是否可以被用来重新编程分化的细胞，使其进入自我更新和/或神经发生状态，从而在成人皮层中提供新生成的神经元。

The cerebral cortex plays a key role in many higher order functions in humans and therefore malformation or damage to the cortex greatly affects our well-being. The cortex is a tissue with very few adult stem cells and therefore has limited capacity to generate new neurons. Decoding the mechanisms that control the self-renewing potential of the cortical progenitors would shed light on the causes of neurodevelopmental disorders, and may also help to develop strategies to repair the damaged and/or aged cortex. My aim in this proposal is to investigate fate-switching mechanisms that change self-renewing progenitors into those capable of generating neurons in the cerebral cortex. Early cortical progenitors are self-renewing and expand the population of progenitors. Subsequently they differentiate into neural progenitors, which undergo a limited number of cell divisions generating neurons. In other words cortical progenitors undergo fundamental changes in their characteristics during early corticogenesis: from self-renewing progenitors to neurogenic progenitors with limited self-renewing capacity but that competently generate neurons. But how the self-renewing and neurogenic progenitor fates are determined and how the transition processes regulated remains an important but unsolved question. Previously I have found that Fgf10, one of the fibroblast growth modulates differentiation of self-renewing to neurogenic progenitors. Based in my initial finding, I aim to identify novel factors determining the fate of self-renewing, neurogenic progenitors and its transition. Determining the underlying mechanisms that control the decision of the neural progenitors to renew or differentiate is very important for at least two reasons. Firstly, balancing self-renewing proliferation and differentiation of neural progenitors is a crucial developmental mechanism to ensure proper growth of the nervous systems. Impairment of progenitor self-renewal results in immature and reduced brain growth, whilst uncontrolled over-proliferation often causes oversized brains and/or cancers. Secondly, the use of stem/progenitor cells offers enormous potential to develop novel strategies to repair damaged nervous systems with little natural regenerative capacity. I firmly believe that the study proposed here will provide new findings to explain fundamental characteristics of cortical progenitors: self-renewing or competent for neurogenesis. This study will provide insights into the genetic program of cortical progenitors that determines their self-renewal potential and neurogenic competency. As the adult cortex has little potential for neurogenesis due of the lack of neural progenitors, developing a regenerative medicine approach is crucial for repair of the cortex injured by various mechanical damages, ischemia, or neurodegenerative diseases. Identifying and characterizing key factors of cortical progenitor differentiation as proposed here will not only shed light on the fundamental mechanisms of neural progenitor differentiation, but may provide us with genetic tools or help to discover drugs that enable direct reprogramming of in vivo differentiated cells (which can no longer regenerate neurons) into neurogenic or self-renewing progenitors. In a following project, I will test the possibility of whether my candidate genes could be utilized to reprogram differentiated cells into self renewal and/or neurogenic states that may provide newly generating neurons in the adult cortex.