Cell segregation in gastrulation: the role of cell fate specification

多细胞生物的发展是由模式化和形态发生的密切相关的活动驱动的。虽然模式化表示细胞命运在空间和时间中的产生和组织，但形态发生包括生物体形成的过程。多细胞生物的形态发生通常涉及其组成细胞的数量、大小、形状和位置的有组织的变化。有越来越多的证据表明，细胞命运规格决定细胞的形态发生潜力，相反，细胞形态发生影响细胞命运规格和维护1。然而，细胞命运规范和形态发生之间的动态相互作用，在一个发展中的有机体才刚刚开始被阐明。在大多数多细胞生物的发育中，第一个主要的形态发生过程是原肠胚形成。在原肠胚形成中，祖细胞分离成不同的细胞群，产生不同的胚层：外胚层、中胚层和内胚层2。胚层的形成和空间组织在两栖动物胚胎中得到了最广泛的研究，涉及细胞迁移和嵌入之间复杂的相互作用3。Townes和Holtfreter在上个世纪中期进行的精液研究表明，加入单细胞悬浮液的原代胚层祖细胞具有显著的自组织成不同胚层的能力，这些胚层的相对位置类似于它们的胚胎起源4。这种自组织能力的胚层祖细胞已被解释的差异，其粘附性能5，虽然具体的贡献差异细胞粘附，而不是其他细胞特性，如细胞皮质张力和细胞迁移，在原肠胚形成过程中胚层形成仍然不清楚6。此外，虽然通过不同的细胞粘附和/或皮质张力解释祖细胞分离和胚层形成的模型通常假设每种祖细胞类型显示确定其特定形态发生潜力的不变和均匀的特性7 -9，但体外和体内观察表明，祖细胞在胚层形成期间经历细胞命运特化和分化的高度动态变化10 -12。在这个跨学科的研究提案中，我们将确定祖细胞命运规范之间的关系<$可逆的过程中，胚盘细胞成为能够分化成外胚层，中胚层和内胚层细胞<$和祖细胞接触形成驱动胚层形成原肠胚形成。我们将确定如何祖细胞的命运规范和细胞间接触的形成在原肠胚形成过程中相互影响，以及它们的相互作用如何影响祖细胞分离和组织的组织。 为此，我们将遵循简化的方法，首先使用最小的体外细胞，

The development of multicellular organisms is driven by the intimately connected activities of patterning and morphogenesis. While patterning denotes the generation and organization of cell fates in space and time, morphogenesis encompasses the processes by which the organism takes shape. Morphogenesis of multicellular organisms typically involves organized changes in the number, size, shape and position of their constituent cells. There is mounting evidence that cell fate specification determines the morphogenetic potential of cells, and conversely, that cell morphogenesis influences cell fate specification and maintenance1. However, the dynamic interplay between cell fate specification and morphogenesis within a developing organism has only begun to be elucidated. The first major morphogenetic process in the development of most multicellular organisms is gastrulation. In gastrulation, progenitor cells segregate into distinct population of cells that give rise to the different germ layers ¿ ectoderm, mesoderm and endoderm2. The formation and spatial organization of germ layers have been most extensively studied in amphibian embryos and involve a complex interplay between cell migration and intercalation3. Seminal studies by Townes and Holtfreter from the middle of the last century have demonstrated that primary germ layer progenitor cells taken into single cell suspensions have the remarkable capacity to self-organize into distinct germ layers, the relative position of which resembles their embryonic origin4. This self-organizing capacity of germ layer progenitor cells has been explained by differences in their adhesive properties5, although the specific contribution of differential cell adhesion, as opposed to other cell properties such as cell cortex tension and cell migration, to germ layer formation during gastrulation remains unclear6. Moreover, while models that explain progenitor cell segregation and germ layer formation by differential cell adhesion and/or cortex tension commonly assume that each progenitor cell type displays invariant and uniform properties determining its specific morphogenetic potential7-9, observations made in vitro and in vivo suggest that progenitor cells undergo highly dynamic changes in cell fate specification and differentiation during germ layer formation10-12. In this interdisciplinary research proposal, we will determine the relationship between progenitor cell fate specification ¿ the reversible process by which blastoderm cells become capable of differentiating into ectoderm, mesoderm and endoderm cells ¿ and progenitor cell-cell contact formation in driving germ layer formation during gastrulation. We will determine how progenitor cell fate specification and cell-cell contact formation influence each other during gastrulation, and how their interaction influences progenitor cell segregation and tissue organization. To this end, we will follow a reductionist approach and first use minimal in vitro cel