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Judith A. West-Mays, Trevor Williams, Erin Bassett; Redundant Roles for Transcription Factors AP-2α and AP-2β in Amacrine and Horizontal Cell Development. Invest. Ophthalmol. Vis. Sci. 2011;52(14):6016.
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Our previous studies in mouse models have demonstrated a requirement for transcription factor AP-2α (Tcfap2a) in the development of multiple ocular tissues, including the lens, cornea and more recently, the optic cup. Although we have demonstrated that AP-2α is expressed in post-mitotic developing and mature amacrine cells, we failed to detect retinal defects in conditional knockouts with neural retina (NR)-specific deletion of Tcfap2a. However, the closely related family member AP-2β showed a spatiotemporal expression pattern in the NR that resembled, and significantly overlapped with, that of AP-2α. We therefore created double mutants lacking both Tcfap2a and Tcfap2b in the developing NR, in order to examine their potentially redundant roles in retinogenesis.
Double Tcfap2a/b retinal mutants with both Tcfap2a and Tcfap2b deleted from the developing retina were generated by crossing retina-specific Tcfap2a conditional knockouts onto a Tcfap2b germ-line knockout background. The developing NR was examined using histological and immunofluorescent techniques, until the death of double mutants at birth.
In addition to amacrine cells, AP-2α and AP-2β were also co-expressed in horizontal cells, although AP-2α expression was only transiently detected in immature horizontal cells. Tcfap2a/b-deficient retinas had multiple defects that were not detected upon deletion of either family member alone. These included a near complete lack of horizontal cells, assessed by loss of the horizontal cell markers PROX1, LIM1, PGP9.5 and neurofilament medium chain. Additionally, amacrine cells were misplaced and did not begin to form orderly mosaics. By late embryogenesis, BHLHB5-positive GABAergic amacrines failed to position themselves within the inner nuclear layer, and the SOX2/ISL1-positive cholinergic amacrine cells did not achieve the regular mosaic spacing observed in control littermates.
This work demonstrates critical overlapping roles for AP-2α and AP-2β in neural retinogenesis. Our studies of double Tcfap2a/b retinal mutants suggest that AP-2α/β influences the intrinsic programs required for amacrine and horizontal cell development.
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