Investigating the mechanisms for building the embryonic body plan: harnessing a paradigm for cell differentiation

胚胎发育的基本工作是在适当的地点和时间，从几个相同的细胞开始，构建由数百种不同类型的细胞组成的成人身体。如果我们能准确地知道这是如何发生的，我们就能在培养皿中控制这一过程，产生可移植的细胞，以修复退化性疾病和损伤中的损伤。在有脊椎的动物中，除了头部的细胞外，所有的细胞类型都是由胚胎尾部的一组未分化的细胞（神经中胚层祖细胞）形成的，从颈部到尾部依次形成脊髓、肌肉和骨骼。在此期间，细胞必须在不同类型之间做出选择，并且通常具有比其最终命运更大的潜力（一种称为“可塑性”的特性），并且只有在之后才不可逆转地承诺给定的细胞身份。我们发现，随着时间的推移，神经中胚层祖细胞会逐渐成熟，然后是颈部、胸腔、下椎骨和可选的尾巴。我们认为这种成熟过程对于沿头尾轴形成的不同细胞类型是重要的。我们已经找到了培养这些细胞的条件，并将在培养物中测试分子，我们之前的工作表明，这些分子对使这些祖细胞成熟很重要。我们将检查在不同成熟阶段由祖细胞形成的细胞类型是否具有不同的功能。我们还将通过研究单个细胞的可塑性，以及在平行细胞中，研究细胞中可以改变身份和不能改变身份的活跃基因的不同，来发现细胞是如何形成特定细胞类型的。我们将测试这些差异活性基因的丧失或获得是否会改变细胞的命运。

The fundamental job of embryo development is to build the adult body, made of hundreds of different kinds of cell, starting with a few identical cells, at the right place and time. If we were to know precisely how this happens, we could control this process in a dish to generate cells that could be transplanted to repair damage in degenerative disease and injury. In animals with a backbone, all the cell types except those in the head form from a set of unspecialised cells (neuromesodermal progenitors) at the tail end of the embryo, progressively laying down the spinal cord, muscles and skeleton in sequence from neck to tail. During this period, cells have to decide between alternative types and typically have a greater potential than their eventual fate (a property called 'plasticity') and only later irreversibly commit to a given cell identity. We have found that neuromesodermal progenitors mature over time as they produce the neck, then the ribcage, lower vertebrae and optional tail. We propose that this maturation process is important for the different cell types formed along the head-to-tail axis. We have found conditions to culture these cells, and will test molecules in culture that our previous work has suggested is important for making these progenitors mature. We will check if the cell types formed from progenitors at different stages of maturity have different functions. We will also find out how cells commit to given cell types by studying plasticity in individual cells, and, in parallel cells, the different genes that are active in cells that can change identity and those that do not. We will test whether loss or gain of any of these differentially-active genes changes cells' ability to commit to their fates.