Teasing apart the cellular and molecular pathways that regulate cell size during asymmetric neural precursor cleavages

梳理不对称神经前体分裂过程中调节细胞大小的细胞和分子途径

• 批准号: BB/X00208X/1
• 负责人: Richard Poole
• 金额: $ 74.58万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX00208X%2F1
• 关键词: Teasing; apart; cellular; molecular; pathways

The size of animals can vary enormously, from a blue whale that can reach a length of over 30 meters to some species of parasitic wasp that even as adults are less than a millimetre in length. However it is not just overall size that varies, the cells within our bodies also display a remarkable range of sizes. For certain cell types there is an obvious association between a cells function and its physical dimensions. Muscle cells need to be long and thin to facilitate contraction and skin cells need to be large and spread out to maximise surface area coverage. Size does matter as they say. Much progress has been made in our understanding of the cellular and molecular mechanisms that regulate how specific organs and tissues can increase in size through cell proliferation or individual cell growth. Yet in many animals cell types of different sizes are generated even during early embryogenesis at a period in which cell growth has not yet kicked in. How cell size during early embryonic divisions is regulated is much less well understood and is the focus of this proposal.One mechanism by which cells of different sizes can be generated is known as unequal cell division. This is a cell division where, during the division, the separation of the two cells is asymmetric and generates one large daughter and one small daughter. Misregulation of this type of division has been implicated in various human diseases such as cancer and so it is imperative we gain a deeper understanding of the cellular and molecular mechanisms involved. In my lab we are interested in how neurons are generated. Neurons are a key cell type in both our brain and peripheral nervous system that not only allow us to think but also allow us to sense and respond to our environment. We study the development of neurons during embryonic development of the nematode C. elegans. Many genes and processes are conserved between this nematode and humans and so we can gain important insights into key fundamental biological process by studying this genetic model system. We study the lineage of cells that gives rise to a specific cell - known as a neuroblast - that itself generates neurons. We have discovered two unequal divisions in the precursor cells that generate this neuroblast. Intriguingly and contrary to popular belief, we have been able to show that in our system the cell size differences produced by these unequal divisions do not affect the development or production of neurons. Instead, we find that the same factors that regulate neuronal specification also regulate the unequal cleavages. This suggests that regulation of unequal division via these factors is an important way of producing cell size diversity in the absence of cell growth. Here we propose to exploit the transparency and genetic amenability of C. elegans to follow how various genetic perturbations affect this asymmetric division. We will first determine whether unequal division depends on neighbouring cells or is intrinsically programmed within the cell itself, and how robust it is to changes in overall size. We will then identify the genes directly responsible for unequal division and finally explore how the upstream regulators we identified orchestrate the complex cell biology required to achieve an unequal division plane. A deeper understanding of how cell fate and cell size are coordinated during development, particularly in situations where cell proliferation and cell growth are not possible is crucial to our understanding of how our nervous system develops and how an organism is built.

动物的体型差异很大，从长度可达 30 多米的蓝鲸到某些寄生蜂，即使成年后长度也不足一毫米。然而，不仅仅是整体大小发生变化，我们体内的细胞也表现出显着的大小范围。对于某些细胞类型，细胞功能与其物理尺寸之间存在明显的关联。肌肉细胞需要又长又薄，以促进收缩，皮肤细胞需要较大且展开，以最大限度地扩大表面积覆盖范围。正如他们所说，尺寸确实很重要。我们对调节特定器官和组织如何通过细胞增殖或单个细胞生长增大的细胞和分子机制的理解已经取得了很大进展。然而，在许多动物中，即使在细胞生长尚未开始的早期胚胎发生期间，也会产生不同大小的细胞类型。早期胚胎分裂期间的细胞大小如何调节尚不清楚，这也是本提案的重点。产生不同大小细胞的一种机制被称为不等细胞分裂。这是一种细胞分裂，在分裂过程中，两个细胞的分离是不对称的，并产生一个大的子细胞和一个小的子细胞。这种分裂的失调与癌症等多种人类疾病有关，因此我们必须更深入地了解所涉及的细胞和分子机制。在我的实验室中，我们对神经元是如何产生的感兴趣。神经元是我们大脑和周围神经系统中的关键细胞类型，它不仅使我们能够思考，而且使我们能够感知环境并做出反应。我们研究了线虫胚胎发育过程中神经元的发育。 elegans。这种线虫和人类之间的许多基因和过程是保守的，因此我们可以通过研究这种遗传模型系统来获得对关键基本生物过程的重要见解。我们研究产生特定细胞（称为神经母细胞）的细胞谱系，该细胞本身会产生神经元。我们发现在产生这种神经母细胞的前体细胞中存在两个不相等的分裂。有趣的是，与普遍的看法相反，我们已经能够证明，在我们的系统中，这些不等分裂产生的细胞大小差异不会影响神经元的发育或产生。相反，我们发现调节神经元规范的相同因素也调节不均匀的分裂。这表明通过这些因素调节不均等分裂是在没有细胞生长的情况下产生细胞大小多样性的重要方式。在这里，我们建议利用秀丽隐杆线虫的透明度和遗传适应性来追踪各种遗传扰动如何影响这种不对称分裂。我们将首先确定不等分裂是否取决于邻近细胞，或者是细胞本身内部编程的，以及它对整体大小变化的鲁棒性如何。然后，我们将确定直接负责不等分裂的基因，并最终探索我们确定的上游调节因子如何协调实现不等分裂平面所需的复杂细胞生物学。更深入地了解细胞命运和细胞大小在发育过程中如何协调，特别是在细胞增殖和细胞生长不可能的情况下，对于我们了解神经系统如何发育以及生物体如何构建至关重要。

项目成果

Control of successive unequal cell divisions by neural cell fate regulators determines embryonic neuroblast cell size

神经细胞命运调节剂对连续不均匀细胞分裂的控制决定了胚胎神经母细胞的大小

• DOI: 10.1242/dev.200981
• 发表时间: 2024-01-11
• 期刊: Development (Cambridge, England)
• 作者: Thomas W. Mullan;Terry Felton;Janis Tam;Osama Kasem;Tim J. Yeung;N. Memar;Ralf Schnabel;Richard J. Poole
• 通讯作者: Richard J. Poole