AP‐2α is required after lens vesicle formation to maintain lens integrity

Abstract

Background: Transcription factors are critical in regulating lens development. The AP-2 family of transcription factors functions in differentiation, cell growth and apoptosis, and in lens and eye development. AP-2a, in particular, is important in early lens development, and when conditionally deleted at the placode stage defective separation of the lens vesicle from the surface ectoderm results. AP-2a's role during later stages of lens development is unknown. To address this, the MLR10-Cre transgene was used to delete AP-2a from the lens epithelium beginning at embryonic day (E) 10.5. Results: The loss of AP-2a after lens vesicle separation resulted in morphological defects beginning at E18.5. By P4, a small highly vacuolated lens with a multilayered epithelium was evident in the MLR10-AP-2a mutants. Epithelial cells appeared elongated and expressed fiber cell specific bB1 and g-crystallins. Epithelial cell polarity and lens cell adhesion was disrupted and accompanied by the misexpression of ZO-1, N-Cadherin, and b-catenin. Cell death was observed in the mutant lens epithelium between postnatal day (P) 14 and P30, and correlated with altered arrangements of cells within the epithelium. Conclusions: Our findings demonstrate that AP2a continues to be required after lens vesicle separation to maintain a normal lens epithelial cell phenotype and overall lens integrity and to ensure correct fiber cell differentiation.

The cellular and molecular mechanisms of vertebrate lens development

“…Among multiple candidate proteins, lens epithelial integrity is mediated by E- and N-cadherins and β-catenin ( Pontoriero et al, 2009 ). The early expression of cadherins is regulated by AP-2α (Tfap2a) ( Pontoriero et al, 2008 ), and loss of AP-2α after the formation of the lens vesicle results in the formation of an abnormal multilayered lens epithelium ( Kerr et al, 2014 ). As age-onset cataract is characterized by disrupted lens epithelium function, including epithelial cell loss (see Petrash, 2013 ), the continuation of studies related to lens epithelial homeostasis is crucial for understanding cataractogenesis.…”

Relationship between neural crest cell specification and rare ocular diseases

“…Previous studies have also shown an association between mutations in the Forkhead Box Protein E3 ( Foxe3 ) gene, and abnormal ocular phenotypes including Peters anomaly, microphthalmia, anophthalmia, and iris and retinal coloboma, in addition to sclerocornea (Garcia‐Montalvo et al, ). FOXE3 is expressed in the head ectoderm and lens epithelium of mice and adult mice that are homozygous null for Foxe3 show many features of other aforementioned genetic mutations, including a reduced lens size and a thicker anterior lens epithelium layer compared to controls (Kerr, Zaveri, Robinson, Williams, & West‐Mays, ; Medina‐Martinez et al, ). In addition, some mutants displayed corneolenticular adhesions and abnormally shaped nuclei of fiber cells within the lens, as well as retinal folding, missing corneal endothelium, disarrayed corneal stroma, and a reduction in thickness of the corneal epithelium (Medina‐Martinez et al, ).…”

“…The TFAP2A gene has previously been linked to optic fissure closure defects and retinal abnormalities associated with coloboma, along with coloboma in the retina and choroid, as well as microphthalmia, iris coloboma, and sclerocornea in humans (Gestri et al, ). TFAP2A is a human homolog of AP‐2α, which is part of the activating protein 2 (AP‐2) family of transcription factors, consisting of a range of retinoic acid (RA) responsive proteins that includes AP‐2α, AP‐2β, AP‐2δ, AP‐2γ, and AP‐2ɛ (Bassett et al, ; Eckert, Buhl, Weber, Jäger, & Schorle, ; Kerr et al, ; West‐Mays et al, ). By E8.75, AP‐2α is expressed in the POM surrounding the optic vesicle of wild‐type mice, although expression ceases in this region after E10.5 (Bassett et al, ).…”

“…. TFAP2A is a human homolog of AP-2a, which is part of the activating protein 2 (AP-2) family of transcription factors, consisting of a range of retinoic acid (RA) responsive proteins that includes AP-2a, AP-2b, AP-2d, AP-2g, and AP-2E(Bassett et al, 2007(Bassett et al, , 2010(Bassett et al, , 2012Eckert, Buhl, Weber, Jäger, & Schorle, 2005;Kerr et al, 2014;West-Mays et al, 1999). By E8.75, AP-2a is expressed in the POM surrounding the optic vesicle of wild-type mice, although expression ceases in this region after E10.5(Bassett et al, 2010).…”

A silent mutation in human alpha-A crystallin gene in patients with age-related nuclear or cortical cataract

“…Further in vitro studies showed that R120G mutation causes defective chaperone-like functions in alpha-B protein [10]. Beta-crystallins are expressed from the early developmental stages in the eye lens; their expression continues and increases after birth, so that the highest concentrations are found in the lens cortex [11]. The molecular basis of crystallin alpha B (CRYAB) gene expression has not been completely understood.…”