ROLES OF CHORDIN AND NOGGIN IN CRANIOFACIAL DEVELOPMENT

脊索蛋白和头蛋白在颅面发育中的作用

• 批准号: 6855768
• 负责人: JOHN A KLINGENSMITH
• 金额: $ 38.42万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6855768
• 关键词: alleles; biological signal transduction; bone development; bone morphogenetic proteins; congenital oral /facial /cranial defect; craniofacial; developmental genetics; ectoderm; embryo /fetus cell /tissue; embryogenesis; embryonic stem cell; endoderm; gene expression; gene induction /repression; gene mutation; genetic markers; histogenesis; laboratory mouse; mutant; nucleic acid sequence; phenotype; protein structure function

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.

描述（改编自研究者摘要）：颅面 发育是脊椎动物个体发育中独特复杂的形态发生过程， 创造了进化的可塑性，但也创造了发育的脆弱性。头部 和面部源自许多组织前体，这需要精确的 模式形成、细胞迁移、增殖、凋亡的协调， 和归纳交互以实现功能性目的。许多这样的事件 由分泌的细胞因子介导，其活性必须受到精确调节 以防止不适当的细胞反应。骨形态发生蛋白 （BMP）是一个分泌配体家族，对许多 颅面发育的各个方面，特别是密切相关的蛋白质 BMP2 和 BMP4。他们的活动被认为对成长或 大脑、头骨、垂体等不同组织的图案 腺体、牙齿和面部的前体。来自果蝇的研究和 非洲爪蟾表明 BMP2/4 信号转导很大程度上受 拮抗蛋白，例如 Chordin (Chd) 和 Noggin (Nog)。在青蛙中，CHD 和 Nog促进前部发育，Chd对于正常头部至关重要 斑马鱼的发育。本提案中描述的初步工作表明 这些基因是哺乳动物头部发育所必需的。缺乏 近交遗传背景下的先天性心脏病会导致一组颅面骨骼 和涉及神经嵴衍生物的软组织缺陷，类似于那些 见于某些人类综合症。 Chd 和 Nog 一起需要尽早进行 负责开发，但也专门参与开发 前脑、嘴、鼻子、下颌骨、颅骨的许多骨头和其他 颅面组织。该提案的主要目标是：1）描述 Chd 和 Nog 的时空表达模式以阐明它们在 颅面发育； 2）确定关键部位和时间 使用胚胎干细胞嵌合体对 Chd 和 Nog 在头部诱导中的作用 组织重组体； 3）确定这些基因在生长和发育中的功能 颅面组织的图案化； 4) 评估是否异位BMP 信号传导再现了突变体的颅面缺陷。