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E. A. Bassett, M. Ershadi, T. Williams, J. A. West-Mays; Defects in Patterning and Maintenance of Retinal Domains in AP-2 Knockout Mice. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3735. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Our previous studies have demonstrated a requirement for transcription factor AP-2α in the development of multiple ocular tissues, including the lens, cornea and optic cup. We have shown that, although AP-2α is not expressed in the retinal pigmented epithelium (RPE), AP-2α germ-line knockout (KO) mice exhibit replacement of the RPE by neural tissue that appears to be a duplicated, inverted neural retina (NR). Conditional deletion of AP-2α from the developing NR does not cause retinal defects, suggesting that the optic vesicle/cup in AP-2α KOs fails to receive the correct RPE-specifying signals from non-retinal tissues. To further assess the nature and timing of alterations in the optic vesicle/cup that lead to the replacement of RPE by a duplicated NR, we have examined AP-2α KOs in detail at multiple stages of optic cup development.
Mice heterozygous for the AP-2α gene were used to generate AP-2α KOs at a spectrum of embryonic stages, starting at E9.5. The developing optic cups were examined using histological and immunofluorescent techniques.
At E9.5, optic vesicles (OVs) evaginated from the forebrain of AP-2α KOs, but were mispositioned. In contrast to their wildtype littermates, the anterior portion of the OV (future NR) in AP-2α KOs failed to orient itself correctly with respect to the surface ectoderm and instead predominantly faced the periocular mesenchyme. At this stage, expression of the NR-specific transcription factor Chx10 was delayed in AP-2α KOs, and the RPE determination gene Otx2 was expressed throughout the OV rather than segregating to the dorsal region (presumptive RPE). While the majority of AP-2α KOs were able to form a bilayered optic cup with a NR that showed normal progression of lamination at earlier stages, a portion of the outer layer commonly lost expression of the RPE markers Mitf and Otx2. This region expressed NR markers and did not become thinner and form a pigmented monolayer.
Our studies of AP-2α KO mice show that loss of AP-2α in non-retinal tissues has an early impact on specification of retinal domains, beginning at the OV stage. These non-cell autonomous effects of AP-2α influence both the position of the optic vesicle/cup, and the expression of genes required to specify and maintain the RPE and NR territories. AP-2α KOs continue to provide a useful model for studying the tissue-tissue interactions and signals required for the regionalization of retinal domains.
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