AP 2 AND CRANIOFACIAL DEVELOPMENT

描述（改编自研究者摘要）： 哺乳动物胚胎需要精确调控的基因模式 表情这在一定程度上是通过一个监管网络来实现的， 调节基因表达速率的转录因子。异常 转录因子活性可导致发育异常， 肿瘤发生对这些蛋白质如何起作用的全面分析至关重要 来了解发育和疾病。首席调查员 本学期的目标是了解这些控制机制的背景下， 转录因子AP-2。AP-2基因可能提供了一个链接， 遗传和环境起源或人类出生缺陷。第一、 染色体定位研究表明AP-2是一个潜在的候选者 人类口面裂的基因第二，AP-2表达是响应性的， 致畸剂视黄酸（RA）。这两个观察结果是一致的 与AP-2的模式是表达在许多问题上经历复杂的 形态发生的变化，特别是在神经嵴，额鼻 突和肢芽。此外，AP-2是 指导正常脊椎动物胚胎发生的调控网络。小鼠 AP-2基因的杂合子表现出颅面缺陷，包括 上颌和牙齿畸形。缺乏AP-2等位基因的小鼠 严重和多效性发育异常。特别是，AP-2 基因敲除小鼠表现出露脑畸形和缺乏可识别的脸。详细 研究表明，五个基本的发展计划依赖于AP- 表情这些包括神经管，脸，眼睛，身体的形成 墙和四肢。AP-2是最强大的调节器之一， 颅面发育的证据因此，为了深入了解 人类先天性畸形的起源，这项建议旨在 确定AP-2控制颅面的调节层次 形态发生将实现三个具体目标。首先，顺- 负责表达的作用序列和反式作用因子 AP-2在面部免疫反应中的作用将被确定。这一目标将揭示 信号传导通路对于正常的 AP-2在发育中面部的表达。第二，由于AP-2的作用， 在颅面发育中的作用很难在敲除小鼠中进行研究 （因为形成头部的多个形态发生过程被破坏）， 将产生一种新的小鼠品系，其中AP-2表达在 仅从显影面去除。这个新的动物模型将揭示 AP-2特异性控制的分子和细胞机制 颅面结构第三，AP-2通过的靶基因 对照颅面形态发生将被识别。所有这些 研究将提供有价值的见解， 和颅面畸形。

DESCRIPTION (adapted from the Investigator's abstract): The development of a mammalian embryo requires precisely regulated patterns of gene expression. This is accomplished, in part, by a regulatory network of transcription factors that modulate the rate of gene expression. Aberrant transcription factor activity can lead to developmental abnormalities and oncogenesis. A comprehensive analysis of how these proteins act is vital to understand development and disease. The Principal Investigator's long term goal is to learn about these control mechanisms in the context of the transcription factor AP-2. The AP-2 gene may provide a link between the genetic and environmental origins or human birth defects. First, chromosomal mapping studies have implicated AP-2 as a potential candidate gene for human orofacial clefting. Second, AP-2 expression is responsive to the teratogen retinoic acid (RA). These two observations are consistent with the pattern of AP-2 is expressed in many issues undergoing complex morphogenetic changes, especially in the neural crest, the frontonasal process and the limb bud. Moreover, AP-2 is a vital component of the regulatory network directing normal vertebrate embryogenesis. Mice heterozygous for the AP-2 gene exhibit craniofacial defects including maxillary and dental malformations. Mice that lack both AP-2 alleles have sever and pleiotropic developmental abnormalities. In particular, AP-2 knockout mice exhibit exencephaly and lack recognizable face. Detailed studies indicate that five basic developmental programs rely on AP- expression. These include formation of the neural tube, face, eyes, body wall and limbs. AP-2 is one of the most powerful regulators of craniofacial development so far identified. Therefore, to gain insight into the origin of human congenital malformations, this proposal seeks to determine the regulatory hierarchy by which AP-2 controls craniofacial morphogenesis. Three specific aims will be undertaken. First, the cis- acting sequences and trans-acting factors responsible for the expression of AP-2 in the facial prominences will be determined. This aim will reveal the signal transduction pathways that are critical for the normal expression of AP-2 in the developing face. Second, since the role of AP-2 in craniofacial development is difficult to study in the knockout mouse (because multiple morphogenic processes shaping the head are disrupted), a novel strain of mouse will be generated in which AP-2 expression in removed only from the developing face. This new animal model will reveal the molecular and cellular mechanisms by which AP-2 specifically controls craniofacial formation. Third, the target genes through which AP-2 controls craniofacial morphogenesis will be identified. Together, these studies will provide valuable insight into both normal facial development and craniofacial deformity.