Role of AP-2 genes in development of the lens

描述（由申请人提供）：在胚胎发生期间，眼透镜从胚胎视网膜和上覆的外胚层之间的相互作用中发育，其形成对于正常的眼睛发育至关重要。例如，透镜发育所必需的基因如Pax 6的突变不仅导致白内障，而且还导致眼睛的其他先天性畸形，包括无虹膜、角膜缺损和小眼。虽然Pax 6基因突变导致了一些眼前节异常的病例，但大多数受影响家庭的遗传原因仍然未知。鉴定眼睛发育的其他关键调节因子及其功能对于进一步分离候选疾病基因是必要的。在上一个资助期间，转录因子AP-2a（激活蛋白-2）被确定为早期眼睛和透镜发育的重要调节因子。在小鼠中AP-2a基因的缺失导致透镜与上覆外胚层的持续粘附，这是一种类似于Pax 6突变体中报道的表型。AP-2a在转基因小鼠（aA-AP-2a）的透镜中的异位表达导致纤维细胞伸长和迁移的抑制以及纤维细胞去核。移行区的缺损与钙粘蛋白表达增加和MIP表达延迟有关。总之，这些发现导致了AP-2基因通过调节参与细胞粘附和/或细胞周期的基因和信号通路来控制透镜诱导和分化的假设。此外，在AP-2突变体透镜中Pax 6表达改变。Pax 6还被证明调节细胞周期和粘附分子的表达，并且突变表型与AP-2的表型相关。因此，进一步提出AP-2和Pax 6参与共同的发育途径以调节彼此的表达，和/或共调节参与透镜发育和分化的下游基因。许多遗传靶向的方法，包括转基因，双和条件敲除小鼠，将被用来确定AP-2基因的具体功能，以及它们如何在信号通路中与已知的（Pax 6）蛋白参与透镜的发展。

DESCRIPTION (provided by applicant): During embryogenesis the ocular lens develops from an interaction between the embryonic retina and overlying ectoderm and its formation is critical for normal eye development. For example, mutations in genes essential to lens development such as Pax6, not only result in cataracts, but cause additional congenital malformations of the eye including aniridia, corneal defects and microphthalmia. Although mutations in Pax6 are responsible for a number of cases of anterior segment anomalies, the genetic cause for the majority of affected families remains unknown. Identification of additional critical regulators of eye development and their function is necessary to further isolate candidate disease genes. During the previous funding period, transcription factor AP-2a (Activating Protein-2) was identified as an important regulator of early eye and lens development. Deletion of the AP-2a gene in mice resulted in a persistent adhesion of the lens to the overlying ectoderm, a phenotype resembling that reported in Pax6 mutants. Ectopic expression of AP-2a in the lens of transgenic mice (aA-AP-2a) resulted in an inhibition of fiber cell elongation and migration and in fiber cell denucleation. The defects were correlated with expanded cadherin expression and delayed MIP expression in the transitional zone. Together, these findings have led to the hypothesis that the AP-2 genes control lens induction and differentiation through the regulation of genes and signaling pathways involved in cell adhesion and/or the cell cycle. In addition, Pax6 expression was altered in the AP-2 mutant lens. Pax6 has also been shown to regulate the expression of cell cycle and adhesion molecules and mutant phenotypes are correlated with that of AP-2. Thus, it is further proposed that, AP-2 and Pax6 participate in common developmental pathways to regulate the expression of each other, and/or co-regulate downstream genes involved in lens development and differentiation. A number of genetically targeted approaches, including transgenic, double and conditional knockout mice, will be employed to determine the specific function of the AP-2 genes and how they interact in signaling pathways with known (Pax6) proteins involved in lens development.