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

动物的体型差异很大，从蓝鲸的体长可达30多米，到某些种类的寄生蜂，成年后体长也不到一毫米。然而，不仅仅是整体大小不同，我们体内的细胞也显示出显著的大小差异。对于某些类型的细胞，细胞的功能与其物理尺寸之间有明显的联系。肌肉细胞需要又长又细以促进收缩，皮肤细胞需要又大又分散以最大限度地覆盖表面积。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而增加大小的细胞和分子机制的理解取得了很大进展。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时期，也会产生不同大小的细胞类型。在早期胚胎分裂过程中，细胞大小是如何被调控的，目前还不太清楚，这也是本研究的重点。产生不同大小细胞的一种机制被称为不均匀细胞分裂。这是一个细胞分裂，在分裂过程中，两个细胞的分离是不对称的，产生一个大的子细胞和一个小的子细胞。这种类型分裂的错误调控与各种人类疾病（如癌症）有关，因此我们必须对所涉及的细胞和分子机制有更深入的了解。在我的实验室里，我们感兴趣的是神经元是如何产生的。神经元是我们大脑和周围神经系统中的一种关键细胞类型，它不仅允许我们思考，还允许我们感知和响应我们的环境。我们研究了秀丽隐杆线虫胚胎发育过程中神经元的发育。许多基因和过程在这种线虫和人类之间是保守的，因此我们可以通过研究这种遗传模型系统来获得对关键的基本生物学过程的重要见解。我们研究产生一种特定细胞的细胞谱系，这种细胞被称为神经母细胞，它本身产生神经元。我们在产生神经母细胞的前体细胞中发现了两次不相等的分裂。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，由这些不平等分裂产生的细胞大小差异并不影响神经元的发育或产生。相反，我们发现调节神经元规格的相同因素也调节不均匀分裂。这表明，通过这些因子调节不均匀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途径。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跟踪各种遗传扰动如何影响这种不对称分裂。我们将首先确定不均匀分裂是取决于邻近细胞还是细胞本身内在的程序，以及它对整体大小变化的适应性。然后，我们将确定直接负责不平等分裂的基因，并最终探索我们确定的上游调节因子如何协调复杂的细胞生物学，以实现不平等分裂平面。更深入地了解细胞命运和细胞大小在发育过程中是如何协调的，特别是在细胞增殖和细胞生长不可能的情况下，这对我们理解神经系统是如何发育的以及生物体是如何构建的至关重要。

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.