THE ROLE OF AP-2 IN CRANIOFACIAL DEVELOPMENT

描述(申请人提供)：复杂的多细胞生物体的发展需要精确调控的基因表达模式。我们的长期目标是在AP-2转录因子家族，特别是Tcfap2a的背景下了解这些控制机制。这种基因可能在人类出生缺陷的遗传和环境起源之间提供了联系。首先，染色体定位研究表明，Tcfap2a是人类口裂的潜在候选基因。其次，Tcfap2a的表达对致畸剂维甲酸有反应。这两个观察结果与在脊椎动物胚胎发育过程中检测到的Tcfap2a表达模式一致。Tcfap2a在许多经历复杂形态发生变化的组织中都有表达，尤其是神经脊、面部和肢芽。此外，Tcfap2a是指导正常脊椎动物胚胎发生的调控网络的重要组成部分。携带Tcfap2a基因杂合子的小鼠会出现包括上颌弯曲在内的头面部缺陷。Tcfap2a基因缺失的小鼠有严重的发育异常：脑外畸形，而且它们没有可识别的脸。详细的研究表明，有六个基本的发育程序依赖于Tcfap2a：神经管、面部、眼睛、体壁、心脏和四肢的形成。Tcfap2a是一种强大的颅面发育调节剂。因此，为了深入了解人类先天畸形的起源，特别是CLIP，这一建议试图确定Tcfap2a控制颅面形态发生的调控等级。将实现三个具体目标。首先，将确定负责Tcfap2a在面部表达的顺式作用序列和反式作用因子。这一目的将揭示Tcfap2a在发育面孔中正常表达的关键信号转导途径。其次，由于Tcfap2a在颅面发育中的作用在空白小鼠中很难研究(因为头部的多个形态发生过程被破坏)，因此将产生一种新的小鼠品系，其中Tcfap2a的表达仅从发育中的面部移除。这一新的动物模型将揭示Tcfap2a特异性控制颅面形成的分子和细胞机制。第三，将确定Tcfap2a控制颅面形态发生的靶基因。总之，这些研究将为正常面部发育和颅面畸形提供有价值的见解。

DESCRIPTION (provided by applicant): The development of a complex multicellular organism requires precisely regulated patterns of gene expression. Our long-term goal is to learn about these control mechanisms in the context of the AP-2 family of transcription factors, especially Tcfap2a. This gene may provide a link between the genetic and environmental origins of human birth defects. First, chromosomal mapping studies have implicated Tcfap2a as a potential candidate gene for human orofacial clefting. Second, Tcfap2a expression is responsive to the teratogen retinoic acid. These two observations are consistent with the pattern of Tcfap2a expression detected during vertebrate embryogenesis. Tcfap2a is expressed in many tissues undergoing complex morphogenetic changes, especially the neural crest, the face and the limb bud. Moreover, Tcfap2a is a vital component of the regulatory network directing normal vertebrate embryogenesis. Mice heterozygous for the Tcfap2a gene exhibit craniofacial defects including maxillary bending. Tcfap2a-null mice have severe developmental abnormalities: exencephaly and they lack a recognizable face. Detailed studies indicate that six basic developmental programs rely on Tcfap2a: formation of the neural tube, face, eyes, body-wall, heart, and limbs. Tcfap2a is a powerful regulator of craniofacial development. Therefore, to gain insight into the origin of human congenital malformations, especially CLIP, this proposal seeks to determine the regulatory hierarchy by which Tcfap2a controls craniofacial morphogenesis. Three Specific Aims will be undertaken. First, the cis-acting sequences and trans-acting factors responsible for the expression of Tcfap2a in the face will be determined. This aim will reveal the signal transduction pathways that are critical for the normal expression of Tcfap2a in the developing face. Second, since the role of Tcfap2a in craniofacial development is difficult to study in the null mouse (because multiple morphogenic processes shaping the head are disrupted), a novel strain of mouse will be generated in which Tcfap2a expression is removed only from the developing face. This new animal model will reveal the molecular and cellular mechanisms by which Tcfap2a specifically controls craniofacial formation. Third, the target genes through which Tcfap2a controls craniofacial morphogenesis will be identified. Together, these studies will provide valuable insight into both normal facial development and craniofacial malformations.