AP-2αTranscription Factor Is Required for Early Morphogenesis of the Lens Vesicle

Abstract

AP-2 transcription factors are a family of retinoic acid-responsive genes, which are involved in complex morphogenetic processes. In the current study, we determine the requirement for AP-2alpha in early morphogenesis of the eye by examining the nature of the ocular defects in AP-2alpha null and chimeric mice. AP-2alpha null embryos exhibited ocular phenotypes ranging from a complete lack of eyes (anophthalmia) to defects in the developing lens involving a persistent adhesion of the lens to the overlying surface ectoderm. Two genes involved in lens development and differentiation, Pax6 and MIP26 were also misexpressed. AP-2alpha mutants also exhibited defects in the optic cup consisting of transdifferentiation of the dorsal retinal pigmented epithelium into neural retina and the absence of a defined ganglion cell layer. Newly generated chimeric embryos consisting of a population of AP-2alpha-/- and AP-2alpha+/+ cells exhibit ocular defects similar to those seen in the knockout embryos. Immunolocalization of AP-2 proteins (alpha, beta, and gamma) to the normal developing eye revealed both unique and overlapping expression patterns, with AP-2alpha expressed in a number of the ocular tissues that exhibited defects in the mutants, including the developing lens where AP-2alpha is uniquely expressed. Together these findings demonstrate a requirement for AP-2alpha in early morphogenesis of the eye.

Genetic and epigenetic mechanisms of gene regulation during lens development

“…Inactivation of Raldh2, expressed in the optic vesicle between E8.5 and E9.5, disrupted optic cup and lens vesicle formation (Mic et al, 2004) and corneal-lenticular stalks are found in RXRα -/-; RARγ -/-compound mice (Kastner et al, 1994). Interestingly, the activity of a retinoic acid activated reporter construct is reduced in the lens placode of the Pax6 -/-mouse (Enwright and Grainger, 2000) and one of the possible targets of retinoic acid signaling in lens is the transcription factor AP-2α (West-Mays et al, 1999).…”

Expression of AP‐2δ in the developing chick retina

“…AP-2␣ knockout mice die perinatally and exhibit severe defects in cranial and body wall closure and skeletal structures (Schorle et al, 1996;Zhang et al, 1996;West-Mays et al, 1999). The ocular defects in these mice are so severe and appear so early, that it has not been possible to evaluate the function of AP-2␣ in retinal development.…”

AP2α alters the transcriptional activity and stability of p53

“…The AP2 factors are developmentally regulated, retinoic acid-inducible genes that orchestrate a variety of cell processes including apoptosis, cell growth and tissue differentiation during embryogenesis (Zhang et al, 1996;Moser et al, 1997). Studies in mice have indicated an important role of AP2 factors in the development of neural crest, epidermal, placental and urogenital tissues (Zhang et al, 1996;Moser et al, 1997;Nottoli et al, 1998;West-Mays et al, 1999;Hilger-Eversheim et al, 2000). Early in embryogenesis, AP2a null/null mice have failure of cranial neural-tube closure and defects in cranial ganglia development (Zhang et al, 1996).…”

“…Later in embryogenesis, the mice develop craniofacial defects and thoraco-abdominoschisis with deformed or absent skeletal bones. A variety of ocular phenotypes have also been described including anophthalmia or abnormal lens morphogenesis (Nottoli et al, 1998;West-Mays et al, 1999). The AP2b null/null mouse phenotype is associated with normal glomerular and tubular differentiation, but at the end of embryonic development, the mice develop massive apoptotic death of the collecting duct and distal tubular epithelia (Moser et al, 1997).…”