Alk8/BMP Signals and Pharyngeal Arch Morphogenesis

Alk8/BMP 信号和咽弓形态发生

• 批准号: 6610670
• 负责人: TRACIE L FERREIRA
• 金额: $ 13.5万
• 依托单位: ADA FORSYTH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6610670
• 关键词: apoptosis; biological signal transduction; bone morphogenetic proteins; cartilage development; confocal scanning microscopy; craniofacial; gene expression; green fluorescent proteins; histogenesis; immunocytochemistry; in situ hybridization; neural crest; oral pharyngeal; polymerase chain reaction; protein localization; protein structure function; transforming growth factors; zebrafish

DESCRIPTION (provided by applicant): Cranial Neural crest cells (CNC) are an embryonic population of multipotent precursor cells that give rise to craniofacial cartilage and bone in the head. Understanding the mechanisms responsible for specification, migration and differentiation of the CNC involves characterizing multiple signaling pathways that converge to regulate expression of effectors genes. Recently, we have shown that Alk8, a novel Type 1 TGF-beta family member receptor, participates in Bmp signaling pathways and influences mediolateral positioning of CNC's and dorsoventral (DV) patterning of pharyngeal arch cartilages. The goal of this proposal is to define the role of Alk8 and Bmp signaling in pharyngeal arch morphogenesis and potential roles in specification of the neural crest. Zebrafish are in ideal vertebrate model for these studies because the embryos are transparent, easy to genetically manipulate, and the craniofacial skeleton is well formed within 5 days. To place Alk8 signals into the larger context of the multiple pathways regulating arch development, Specific Aim 1 is designed to screen for alk8 downstream signaling components. The results of this screen will provide a pool of potential candidates for CNC specific signaling events. The experiments outlined in Specific Aim 2 will characterize the temporospatial expression patterns of Alk8. These studies will be coupled with promoter analysis to determine regulatory elements driving tissue specific and/or temporally restricted Alk8 expression. Specific Aim 3, mosaic analysis, will determine the cell autonomous/non-autonomous effect that Alk8 experts on the neural crest. Specific Aim 4 will examine pharyngula stages of embryogenesis to determine if apoptosis or later chondrogenic defects contribute to defects in cartilage formation. These experiments will lend insight into the mechanisms specifying the neural crest, and will aid in development of therapies for congenital disorders such as Treacher Colins syndrome, Hirschsprung's disease and Cleidocranial dysplasia.

描述（由申请人提供）：颅神经crest细胞（CNC）是多能前体细胞的胚胎群体，可引起头部颅面软骨和骨骼。了解负责指定，迁移和分化的机制涉及表征多个信号通路，这些信号通路会融合以调节效应子基因的表达。最近，我们已经表明，ALK8是一种新型的1型TGF-beta家族成员受体，它参与了BMP信号通路，并影响了CNC和背腹（DV）咽弓软骨的中外侧定位。该提案的目的是定义ALK8和BMP信号传导在咽弓形态发生中的作用，并在神经rest的规范中的潜在作用。对于这些研究，斑马鱼是理想的脊椎动物模型，因为胚胎是透明的，易于遗传操作，并且颅面骨骼在5天内形成良好。要将ALK8信号放置在调节拱门开发的多个途径的较大环境中，特定的AIM 1旨在筛选ALK8下游信号传导组件。该屏幕的结果将为CNC特定信号事件提供一组潜在的候选者。特定目标2中概述的实验将表征ALK8的暂时性表达模式。这些研究将与启动子分析相结合，以确定驱动组织特异性和/或时间限制ALK8表达的调节元素。具体目标3，马赛克分析将确定ALK8专家对神经rest的细胞自主/非自主效应。具体目标4将检查胚胎发生的咽阶段，以确定凋亡或后来的软骨原性缺陷是否有助于软骨形成的缺陷。这些实验将深入了解指定神经rest的机制，并有助于开发先天性疾病的疗法，例如Treacher Colins综合征，Hirschsprung氏病和Cleidocranial densblasia。