RNA dynamics in the developing mouse face

颅面形态发生是一个复杂的过程，需要六个不同的面部隆起协调的增殖、运动和分化。这一过程的复杂性使其容易受到环境和遗传扰动的影响，因此颅面畸形是最常见的出生缺陷之一。面部隆起由一层单层外胚层包裹着一大片神经脊和中胚层来源的间充质细胞组成。来自这一小群外胚层细胞的信号指导和协调底层间充质的行为，并由此产生面部形态发生。改变这些信号过程和组织相互作用的操作对面部发育有严重的后果，导致各种类型的医学上重要的畸形，包括口面部裂伤。因此，对外胚层基因动力学的详细了解是全面描述面部发育的重要组成部分。在这项提案中，一个由多学科组成的团队集合了颅面生物学、小鼠分子遗传学、生物信息学和计算机生物学的专业知识，以获得对哺乳动物早期面部发育的系统生物学水平的了解。 野生型面部隆起的外胚层和间质将在围绕面部形态发生的关键时间点被分离，然后这些分离的组织将被用于在剪接、周转和翻译水平上产生基因表达和翻译后RNA调控的对比动态时空图谱。这些联合研究应该提供一个有价值的资源，详细说明正常面部发育过程中外胚层和间充质的动态相互作用。

Craniofacial morphogenesis is a complex process requiring coordinated proliferation, movement and differentiation of six distinct facial prominences. The complexity of this process leaves it vulnerable to environmental and genetic perturbations, such that craniofacial malformations are one of the most common classes of birth defects. Facial prominences are made up of a mono-layer of ectoderm encasing a large core of neural crest- and mesodermally-derived mesenchymal cells. Signaling from this minor population of ectodermal cells directs and coordinates the behavior of the underlying mesenchyme, and thence facial morphogenesis. Manipulations that alter these signaling processes and tissue interactions have grave consequences for facial development, resulting in various types of medically important dysmorphology including orofacial clefting. Thus a detailed knowledge of geno-dynamics of the ectoderm is an essential component of the overall description of facial development. In this proposal a multi-disciplinary team has been assembled with expertise in craniofacial biology, mouse molecular genetics, bioinformatics and computer biology to gain a Systems Biology level understanding of early mammalian facial development. The ectoderm and the mesenchyme of the wild-type facial prominences will be separated at critical timepoints encompassing facial morphogenesis, then these separated tissues will be used to generate contrasting dynamic spatio-temporal profiles of gene expression and post-translational RNA regulation at the level of splicing, turnover, and translation. These combined studies should provide a valuable resource detailing the dynamic interplay of ectoderm and mesenchyme during normal facial development.