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

皮质祖细胞自我更新和神经源性特征的分子控制

• 批准号: BB/L00562X/1
• 负责人: Setsuko Sahara
• 金额: $ 54.41万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL00562X%2F1
• 关键词: Molecular; control; self; renewal; neurogenic

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.

大脑皮层在人类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会极大地影响我们的健康。皮质是一种成体干细胞很少的组织，因此产生新神经元的能力有限。解码控制皮质祖细胞自我更新潜力的机制将有助于揭示神经发育障碍的原因，并且还可能有助于制定修复受损和/或老化皮质的策略。我此提案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生成神经元的祖细胞。 早期皮质祖细胞能够自我更新并扩大祖细胞数量。随后，它们分化成神经祖细胞，神经祖细胞经历有限次数的细胞分裂，产生神经元。换句话说，皮质祖细胞在早期皮质发生过程中其特征经历了根本性变化：从自我更新祖细胞到自我更新能力有限但能够产生神经元的神经源性祖细胞。但自我更新和神经源性祖细胞的命运是如何决定的以及转变过程如何调节仍然是一个重要但尚未解决的问题。之前我发现 Fgf10（成纤维细胞生长之一）调节自我更新向神经源性祖细胞的分化。根据我最初的发现，我的目标是确定决定自我更新、神经源性祖细胞及其转变命运的新因素。 确定控制神经祖细胞更新或分化决策的潜在机制非常重要，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确保神经系统正常生长的关键发育机制。祖细胞自我更新受损会导致大脑不成熟和生长减少，而不受控制的过度增殖通常会导致大脑过大和/或癌症。其次，干/祖细胞的使用提供了开发新策略来修复自然再生能力很少的受损神经系统的巨大潜力。 我坚信，这里提出的研究将提供新的发现来解释皮质祖细胞的基本特征：自我更新或有能力进行神经发生。这项研究将深入了解皮质祖细胞的遗传程序，该程序决定了其自我更新潜力和神经发生能力。由于成人皮质缺乏神经祖细胞，几乎没有神经发生的潜力，因此开发再生医学方法对于修复因各种机械损伤、缺血或神经退行性疾病而受损的皮质至关重要。本文提出的识别和表征皮质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能够将体内分化细胞（不能再再生神经元）直接重编程为神经源性或自我更新祖细胞的药物。在接下来的项目中，我将测试我的候选基因是否可用于将分化细胞重新编程为自我更新和/或神经源状态，从而在成人皮质中提供新生成的神经元。

项目成果

Genetic mechanisms control the linear scaling between related cortical primary and higher order sensory areas.

遗传机制控制相关皮质初级和高级感觉区域之间的线性缩放。

• DOI: 10.7554/elife.11416
• 发表时间: 2015
• 期刊: eLife
• 影响因子: 7.7
• 作者: Zembrzycki A

A common rule governing differentiation kinetics of mouse cortical progenitors.

控制小鼠皮质祖细胞分化动力学的共同规则。

• DOI: 10.1073/pnas.1916665117
• 发表时间: 2020
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Sahara,Setsuko;Kodama,Takashi;Stevens,CharlesF
• 通讯作者: Stevens,CharlesF

Generation and analysis of an improved Foxg1-IRES-Cre driver mouse line.

• DOI: 10.1016/j.ydbio.2016.02.011
• 发表时间: 2016-04-01
• 期刊: Developmental biology
• 影响因子: 2.7
• 作者: Kawaguchi D;Sahara S;Zembrzycki A;O'Leary DDM
• 通讯作者: O'Leary DDM

Tuba8 Drives Differentiation of Cortical Radial Glia into Apical Intermediate Progenitors by Tuning Modifications of Tubulin C Termini

Tuba8 通过调节微管蛋白 C 末端的修饰来驱动皮质放射状胶质细胞分化为顶端中间祖细胞

• DOI: 10.1016/j.devcel.2020.01.036
• 发表时间: 2020
• 期刊: Developmental Cell
• 影响因子: 11.8
• 作者: Ramos S