Reconstructing fate decisions in the peripheral sensory nervous system of the head

人类和动物都不断受到来自我们环境的信息的轰炸：嗅觉、声音、光线、颜色、味觉，以及不太明显的刺激，如触觉、疼痛和温度。这些信息通过头部的感觉器官和感觉神经节传递到大脑。虽然这些结构在成人中非常多样化，但它们在胚胎发育过程中来自共同的干细胞样祖细胞。拥有共同历史的细胞是如何变得彼此不同的？这是一个令人兴奋的问题，有许多不同的含义。找到答案不仅对理解正常发育如何工作很重要，而且对揭示发育疾病的潜在原因，找到促进细胞损伤后修复的新方法以及指导干细胞分化为感觉器官细胞也很重要。在这个项目中，我们将利用新技术，使我们能够在单个细胞水平上研究数千个细胞，并重建细胞如何在活胚胎中做出决定。首先，我们将使用测量单个细胞（单细胞RNAseq）中基因表达的技术制作细胞图谱。我们将根据它们表达的基因对细胞进行分类，并确定新细胞类型出现的顺序。其次，我们将使用一种称为ATACseq的方法确定不同细胞中的基因表达如何在时间和空间上受到控制。我们将利用这些信息来预测细胞命运决定是如何被调控的。第三，我们将使用一种最近才可用的新技术来重建胚胎中的谱系树。细胞有一个独特的“疤痕”，这是细胞分裂时遗传的；然后对细胞取样，在单细胞水平上检查它们的基因表达谱。通过这种方式，我们可以将细胞的基因特征与其命运联系起来，确定哪些细胞来自相同的祖细胞，哪些细胞来自不同的祖细胞，并使用计算方法揭示真正的谱系关系。最后，我们将整合所有数据来确定新的候选命运决定因素，并将测试它们在发育中的感觉神经系统中的功能。为了实现这些目标，我们汇集了一个跨学科的团队：Streit小组是现代感官发育生物学的专家，而Luscombe小组在生物医学研究前沿的计算方法方面有着长期的专业知识。总之，本项目将以前所未有的深度描述感觉器官和神经节祖细胞及其衍生物的分子特性，重建它们的谱系关系，并确定这种关系是如何控制的。这个项目的力量在于它的跨学科性质，而它的影响超越了发育生物学，进入了再生医学、干细胞生物学和进化。

Humans and animals alike are constantly bombarded with information from our environment: smell, sound, light and colour, taste as well as less obvious stimuli like touch, pain and temperature. This information is transmitted to the brain by the sense organs and sensory ganglia in the head. While these structures are very diverse in adults, they come from common stem-cell-like progenitors during embryo development. How do cells that share a common history become different from each other? This is an exciting question with many different implications. Finding out the answer is not only important to understand how normal development works, but also to unravel the causes underlying developmental diseases, to find new ways to promote repair after cell damage and to direct stem cells to differentiate into sense organ cells.In this project, we will take advantage of new technologies that allow us to study thousands of cells at single cell level and reconstruct how cells make decisions in the living embryo. First, we will make an atlas of cells using a technology that measures gene expression in individual cells (single cell RNAseq). We will categorise cells according to the genes they express and determine the order in which new cell types appear. Second, we will determine how gene expression in different cells is controlled in time and space using an approach called ATACseq. We will use this information to predict a how cell fate decisions are regulated.Third, we will use a novel technique that has only very recently become available to reconstruct lineage trees in the embryo. Cells are marked by a unique 'scar' which is inherited as cells divide; cells are later sampled to examine their gene expression profile at single cell level. This way we can link the gene signature of a cell with its fate, establish which cells arise from the same and from different progenitors and use computational methods to uncover real lineage relationships.Finally, we will integrate all data to identify new candidate fate determinants and will test their function in the developing sensory nervous system.To achieve these aims we bring together an interdisciplinary team: the Streit group are experts in modern sensory developmental biology, while the Luscombe group has long-standing expertise in computational approaches at the forefront of biomedical research.In summary, this project will characterise the molecular properties of sense organ and ganglia progenitors and their derivatives in unprecedented depth, reconstruct their lineage relationship as well as identifying how this is controlled. The power of this project lies its interdisciplinary nature, while its impact reaches beyond developmental biology into regenerative medicine, stem cell biology and evolution.