ROLES OF CHORDIN AND NOGGIN IN CRANIOFACIAL DEVELOPMENT

描述(改编自《调查者摘要》)：头面部 在脊椎动物个体发育中，发育是一个独特的复杂的形态发生过程， 创造了进化的可塑性，但也造成了发育上的脆弱性。头部 和脸是从许多组织前体衍生而来的，这需要精确的 模式形成，细胞迁移，增殖，凋亡， 和感应相互作用，以实现功能目的。这些活动中的许多 是由分泌的细胞因子介导的，其活性必须受到精确的调控 以防止不适当的细胞反应。骨形态发生蛋白 (BMP)是一类分泌的配体，对许多 颅面发育的方方面面，特别是密切相关的蛋白质 BMP2和BMP4。他们的活动被认为是重要的增长或 大脑、头骨、脑下垂体等不同组织的图案 腺体、牙齿和脸部的前体。果蝇和果蝇的研究 非洲爪哇研究表明，BMP2/4信号转导在很大程度上是由 拮抗蛋白，如Chordin(CHD)和Noggin(Nog)。在青蛙、先天性心脏病和 NOG促进前部发育，而CHD是正常头部所必需的 斑马鱼的发育。该提案中描述的初步工作显示 这些基因是哺乳动物头部发育所必需的。缺乏 近亲交配遗传背景的CHD导致一组头面部骨骼 以及涉及神经脊衍生物的软组织缺陷，类似于 出现在某些人类综合征中。CHD和NOG一起是早期需要的 主管开发，但也专门参与开发 前脑、嘴巴、鼻子、下颌骨、头盖骨等 头面部组织。这项提议的主要目的是：1)描述 CHD和NOG的时空表达模式及其在冠心病发病中的作用 2)确定颅面发育的关键部位和时间。 CHD和NOG在胚胎干细胞嵌合体诱导头部中的作用 组织重组；3)确定这些基因在生长和生长中的功能 头面部组织图案化；4)评估异位骨形态发生蛋白 Signal重现了突变体的头面部缺陷。

DESCRIPTION (Adapted from the Investigator's Abstract): Craniofacial development is a uniquely complex morphogenetic process in vertebrate ontogeny, creating evolutionary plasticity but also developmental vulnerability. The head and face are derived from many tissue precursors, which require a precise orchestration of pattern formation, cell migration, proliferation, apoptosis, and inductive interactions to achieve a functional end. Many of these events are mediated by secreted cytokines, whose activity must be precisely regulated to preclude inappropriate cellular responses. Bone Morphogenetic Proteins (BMPs) are a family of secreted ligands which have potent effects on many aspects of craniofacial development, particularly the closely related proteins BMP2 and BMP4. Their activity is thought to be important in the growth or patterning of such diverse tissues as the brain, the skull, the pituitary gland, the teeth, and the precursors of the face. Research from Drosophila and Xenopus indicate that BMP2/4 signal transduction is regulated in large part by antagonistic proteins such as Chordin (Chd) and Noggin (Nog). In frogs, Chd and Nog promote anterior development, and Chd is essential for normal head development in zebrafish. Preliminary work described in this proposal shows that these genes are required for development of the mammalian head. Lack of Chd in an inbred genetic background results in a group of craniofacial skeletal and soft-tissue defects involving neural crest derivatives, similar to those seen in certain human syndromes. Chd and Nog together are required early for head development, but are also involved specifically in development of the forebrain, mouth, nose, mandible, numerous bones of the skull, and other craniofacial tissues. The major aims of this proposal are: 1) to characterize the spatiotemporal expression patterns of Chd and Nog to clarify their roles in craniofacial development; 2) to determine the critical sites and times of action for Chd and Nog in head induction using embryonic stem cell chimeras and tissue recombinants; 3) to determine the functions of these genes in growth and patterning of craniofacial tissues; and 4) to assess whether ectopic BMP signaling reproduces the craniofacial defects of the mutants.