ENVIRONMENTAL CONTROL OF NEURAL CREST DEVELOPMENT

神经嵴发育的环境控制

基本信息

批准号：
2896913
负责人：
JAMES A WESTON
金额：
$ 21.07万
依托单位：
UNIVERSITY OF OREGON
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-05-01 至 2001-05-31
项目状态：
已结题

项目摘要

Our long-term goal is to understand how stable differences in developmental ability are established in the neural crest (NC) cell lineage. When trunk NC cells segregate from neural tube epithelium in vivo, they enter a cell-free, extracellular matrix-rich "migration staging area" (MSA), and then disperse on two distinct migration pathways. Trunk NC cells that disperse early on a medioventral ("medial") pathway between the neural tube and the somites give rise to both neuronal and non- neuronal derivatives. These include sensory, autonomic and enteric neurons, Schwann sheath cells and glia of the peripheral ganglia, and perhaps some late-developing melanocytes in distal locations. In contrast, trunk NC cells that disperse later on a dorsolateral ("lateral") pathway never give rise to neuronal derivatives, but differentiate only as melanocytes (and perhaps other non-neuronal) crest derivatives. We have found that crest-derived melanocyte precursors express c-kit, the receptor for Steel Factor (SLF), and transiently depend on SLF function for survival in vitro. Previous work, by us and others, has also shown that differentiation of melanocytes and other non-neuronal, crest-derived cells is affected both by SLF and by platelet-derived growth factor (PDGF) function, mediated by the receptor PDGFRalpha. To explain why melanocytes arise primarily (or solely) from NC cells on the lateral pathway of mouse embryos, we hypothesize that developmentally-distinct crest-derived cells, which appear at late stages of crest cell dispersal from the MSA , selectively follow the lateral crest-migration pathway where they encounter localized growth/survival cues that they require. To test this hypothesis, we will examine murine embryos during crest cell dispersal, and cultured crest cells at corresponding developmental stages, to learn (a) when and where crest-derived melanocyte precursors first acquire the receptors for Steel factor (c-kit) and platelet-derived growth factor, A- chain (PDGFRalpha), (b) when and where crest cells encounter SLF and PDGF during their initial dispersal in embryonic interstitial spaces, and (c) how mutational perturbation of SLF presentation affects developmental behavior of melanocyte precursors. Specifically, we will: 1. characterize the expression of c-kit and PDGFRalpha in late-migrating (non-neurogenic) crest-derived cells in vitro; 2. determine the distribution of SLF and PDGF on the medial and lateral crest migratory pathways in the embryonic trunk, and the pattern of dispersal of crest-derived melanocyte precursors on these two pathways; and concurrently, 3. characterize the pattern of dispersal and the fate of crest-derived melanocyte precursors when SLF and PDGF function are mutationally perturbed in vivo.

我们的长期目标是了解稳定的差异发育能力是在神经波峰（NC）细胞中建立的血统。当躯干NC细胞从神经管上皮分离时体内，它们进入了无细胞的，细胞外基质富的“迁移分期区域”（MSA），然后分散在两个不同的迁移途径上。树干 NC细胞早期分散在床之间的（内侧”途径上神经管和节点引起神经元和非 - 神经元素衍生物。这些包括感觉，自主和肠神经元，Schwann护套细胞和周围神经节的神经胶质，以及也许在远端的一些晚期黑素细胞。相比之下，躯干NC细胞，后来分散在背外侧（“侧向”）途径上切勿引起神经元衍生物，而是区分黑素细胞（也许还有其他非神经元）冠衍生物。我们发现，波峰衍生的黑素细胞前体表达C-Kit，钢因子（SLF）的受体，并瞬时依赖SLF功能用于体外生存。我们和其他人的先前工作也表明黑素细胞和其他非神经元的差异化差异化细胞受SLF和血小板衍生的生长因子（PDGF）的影响功能，由受体PDGFRALPHA介导。解释为什么黑素细胞主要（或仅）来自NC细胞的小鼠横向途径胚胎，我们假设具有发育赋予的波峰衍生的细胞，出现在MSA的Crest细胞分散的后期阶段，有选择地遵循横向冠式移民途径遇到所需的局部增长/生存线索。测试这个假设，我们将检查在波峰细胞扩散期间的鼠类胚胎，和在相应的发育阶段进行培养的冠台细胞，以学习（a）何时何地，何时何地衍生的黑素细胞前体首先获得钢质因子（C-KIT）和血小板衍生的生长因子A-的受体链（PDGFRALPHA），（b）何时何时遇到Crest细胞遇到SLF和PDGF 在最初的散布在胚胎间隙空间中，（c） SLF演示的突变扰动如何影响发展黑素细胞前体的行为。具体来说，我们将： 1。表征c-kit和pdgfralpha在延迟迁移中的表达（非神经生成）在体外衍生的rest衍生细胞； 2。确定SLF和PDGF在内侧和侧面的分布胚胎躯干中的波峰迁移途径和在这两种途径上散布波峰衍生的黑素细胞前体；并同时 3。表征分散的模式和波峰衍生的命运当SLF和PDGF功能是突变时，黑素细胞前体在体内扰动。