Role of AP-2 genes in development of the lens

描述(申请人提供)：在胚胎发育期间，晶状体由胚胎视网膜和覆盖的外胚层之间的相互作用发展而来，它的形成对眼睛的正常发育至关重要。例如，晶状体发育所必需的基因突变，如Pax6，不仅会导致白内障，还会导致额外的眼睛先天性畸形，包括无虹膜、角膜缺陷和小眼球。虽然Pax6基因的突变导致了许多眼前段畸形，但大多数受影响家庭的遗传原因仍不清楚。为了进一步分离候选疾病基因，有必要确定眼睛发育的其他关键调控因子及其功能。在之前的资助期间，转录因子AP-2a(激活蛋白-2)被认为是眼睛和晶状体早期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覆盖的外胚层持续粘连，这种表型与Pax6突变体中报告的表型相似。AP-2a在转基因小鼠(AA-AP-2a)晶状体中的异位表达抑制了纤维细胞的伸长和迁移，并抑制了纤维细胞的脱核。这些缺陷与移行区钙粘蛋白表达增强和MIP表达延迟有关。综上所述，这些发现导致了一种假设，即AP-2基因通过调节参与细胞黏附和/或细胞周期的基因和信号通路来控制晶状体的诱导和分化。此外，AP-2突变型晶状体中Pax6的表达也发生了变化。Pax6也被证明调节细胞周期和黏附分子的表达，突变的表型与AP-2相关。因此，进一步提出，AP-2和Pax6参与共同的发育途径，相互调节彼此的表达，和/或共同调节参与晶状体发育和分化的下游基因。包括转基因、双基因和条件性基因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.