NFkB Targets and Neural Crest Development

神经嵴是脊椎动物的创新，有时被称为第四胚层;神经嵴产生迁移细胞，分化成软骨，黑素细胞，外周神经系统和心脏流出道。神经嵴的缺陷涉及超过400种人类综合征，并导致颅面、心脏、色素沉着、外周和中枢神经系统缺陷。我们的重点一直是环境调节和发育重要的转录因子NF κ B及其在早期胚胎的调控目标。NF κ B活化与环境因素如乙醇的致畸作用有关。影响神经嵴的早期胚胎缺陷是与胎儿酒精综合征（FAS）相关的神经、颅面和牙齿畸形以及不太严重但仍然显著的酒精相关神经发育障碍（ARND）和酒精相关出生缺陷（ARBD）的基础。该提案的目标是更好地理解这些缺陷的分子性质，特别是涉及NF κ B的调节靶点的缺陷。使用爪蛙爪蟾作为模型系统，我们发现NF κ B调节扭曲，snai/1和snai/2（蛞蝓）RNA水平的水平。twist编码bHLH转录因子，snai/1和snai/2编码相关的锌指转录因子Snail 1和Snail 2，这三种转录因子也与肿瘤转移有关。在早期胚胎中，Twist、Snail 1和Snail 2调节彼此的表达，并且是中胚层的形成以及随后的神经嵴的形成、存活和分化所必需的。令人惊讶的是，可以挽救对方的功能表型的损失。有证据表明，一个类似的网络的相互作用可能是活跃的早期小鼠胚胎，争论这个系统的相关性，人类胚胎/神经嵴缺陷。鉴于该项目的可用时间缩短（2年），我们将集中精力于两个修订后的目标，并将推迟使用斑马鱼的比较和细胞迁移研究。通过利用X. Laevis系统，我们将i）定义Twist、SNAI/1和SNAI/2在神经嵴诱导、存活和分化上的独特和互补的中胚层作用，和ii）识别神经嵴特化中胚层信号的时间和空间要求。这些观察结果对于理解一般分子和诱导网络的行为，特别是预防和/或改善神经嵴缺陷具有重要意义。

The neural crest is a vertebrate innovation, sometimes referred to as the fourth germ layer; the neural crest gives rise to migrating cells that differentiate into cartilage, melanocytes, the peripheral nervous system, and the outflow tract of the heart. Defects in the neural crest are involved in over 400 human syndromes and result in craniofacial, heart, pigmentation, peripheral and central nervous system defects. Our focus has been on the environmentally regulated and developmentally important transcription factor NFKB and its regulatory targets in the early embryo. NFKB activation has been implicated in the teratogenic effects of environmental factors such as ethanol. Early embryonic defects impacting the neural crest underlie the neurological, craniofacial, and dental malformations associated with Fetal Alcohol Syndrome (FAS) and the less severe, but still significant alcohol-related neurodevelopmental disorder (ARND) and alcoholrelated birth defects (ARBD). The goal of this proposal is to better understand the molecular nature of these defects, particularly those involving the regulatory targets of NFKB. Using the clawed frog Xenopus as a model system, we found that NFKB regulates the levels of twist, snai/1, and snai/2(slug) RNA levels. twist encodes a bHLH transcription factor, while snai/1 and snai/2 encode the related zinc-finger transcription factors Snail1 and Snail2; these three transcription factors are also implicated tumor metastasis. In the early embryo, Twist, Snail1, and Snail2 regulate one another's expression and are required for the formation of mesoderm and the subsequent formation, survival, and differentiation of the neural crest. Surprisingly, can rescue each other's loss of function phenotypes. There is evidence that a similar network of interactions may be active in the early mouse embryo, arguing for the relevance of this system to human embryonic/neural crest defects. In light of the shortened (2 year) timespan available for this project, we will concentrate our efforts on two revised aims and will delay our comparative and cell migration studies using ebrafish until a later time. By exploiting the experimental strengths of the X. laevis system we will i) define the unique and complementary mesodermal roles of twist, snai/1, and snai/2 on neural crest induction, survival, and differentiation and ii) identify the temporal and spatial requirement for mesodermal signals in neural crest specification. Together these observation should have important implications for understanding the behavior of molecular and inductive networks in general and the prevention and/or amelioration of neural crest defects in particular.