Role of AP-2 genes in development of the lens

描述（由申请人提供）：在胚胎发生过程中，晶状体由胚胎视网膜和上覆的外胚层相互作用而发育，其形成对正常的眼睛发育至关重要。例如，对晶状体发育至关重要的基因突变，如Pax6，不仅会导致白内障，还会导致其他先天性眼睛畸形，包括无虹膜、角膜缺陷和小眼。虽然Pax6基因突变是导致许多前节异常的原因，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。在之前的资助期内，转录因子AP-2a（激活蛋白-2）被确定为早期眼睛和晶状体发育的重要调节因子。在小鼠中，AP-2a基因的缺失导致晶状体与上覆的外胚层持续粘附，这种表型类似于Pax6突变体中报道的表型。AP-2a在转基因小鼠晶状体中的异位表达（aA-AP-2a）导致纤维细胞伸长、迁移和纤维细胞去核受到抑制。这些缺陷与过渡区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基因通过调控参与细胞粘附和/或细胞周期的基因和信号通路来控制晶状体诱导和分化的假设。此外，AP-2突变体晶状体中Pax6的表达也发生了改变。Pax6也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相关。因此，我们进一步提出AP-2和Pax6参与共同的发育通路，相互调控表达，并/或共同调控下游参与晶状体发育和分化的基因。包括转基因、双基因敲除和条件敲除小鼠在内的许多基因靶向方法将被用来确定AP-2基因的特定功能，以及它们如何在信号通路中与参与晶状体发育的已知（Pax6）蛋白相互作用。

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.