AP-2α knockout mice exhibit optic cup patterning defects and failure of optic stalk morphogenesis

Abstract

Appropriate development of the retina and optic nerve requires that the forebrain-derived optic neuroepithelium undergoes a precisely coordinated sequence of patterning and morphogenetic events, processes which are highly influenced by signals from adjacent tissues. Our previous work has suggested that transcription factor activating protein-2 alpha (AP-2alpha; Tcfap2a) has a non-cell autonomous role in optic cup (OC) development; however, it remained unclear how OC abnormalities in AP-2alpha knockout (KO) mice arise at the morphological and molecular level. In this study, we show that patterning and morphogenetic defects in the AP-2alpha KO optic neuroepithelium begin at the optic vesicle stage. During subsequent OC formation, ectopic neural retina and optic stalk-like tissue replaced regions of retinal pigment epithelium. AP-2alpha KO eyes also displayed coloboma in the ventral retina, and a rare phenotype in which the optic stalk completely failed to extend, causing the OCs to be drawn inward to the midline. We detected evidence of increased sonic hedgehog signaling in the AP-2alpha KO forebrain neuroepithelium, which likely contributed to multiple aspects of the ocular phenotype, including expansion of PAX2-positive optic stalk-like tissue into the OC. Our data suggest that loss of AP-2alpha in multiple tissues in the craniofacial region leads to severe OC and optic stalk abnormalities by disturbing the tissue-tissue interactions required for ocular development. In view of recent data showing that mutations in human TFAP2A result in similar eye defects, the current findings demonstrate that AP-2alpha KO mice provide a valuable model for human ocular disease.

Eye Development and Retinogenesis

“…4C). Cross talk between the presumptive lens and retina may be necessary for the proper invagination of both tissues in vivo (Grindley et al 1995;Ashery-Padan et al 2000;Smith et al 2009;Bassett et al 2010).…”

“…Tcfap2a (AP-2a) is expressed in the POM and has been shown to be crucial for the correct positioning of the OV adjacent to the lens placode (Bassett et al 2010). The optic vesicles of mice deficient in Tcfap2a are not positioned correctly in relation to the surface ectoderm and therefore do not receive the correct combinations of extracellular signals, leading to improper regionalization and morphogenesis of the OV/OC in vivo (Bassett et al 2010).…”

“…The optic vesicles of mice deficient in Tcfap2a are not positioned correctly in relation to the surface ectoderm and therefore do not receive the correct combinations of extracellular signals, leading to improper regionalization and morphogenesis of the OV/OC in vivo (Bassett et al 2010). In contrast to the in vitro model, these studies suggest that the positioning of the OV adjacent to the lens placode (LP) in vivo allows the developing OC to receive the correct spatial signals from surrounding tissues for proper regionalization along its axes (Fig.…”

Sma- and Mad-related Protein 7 (Smad7) Is Required for Embryonic Eye Development in the Mouse

“…Ap2␣ is expressed in POM and is crucial for correct positioning of the optic vesicle. The Ap2␣ mutant mouse has defective POM with a reduction of Pitx2 (50). The optic vesicle in the Ap2␣ mutant mouse cannot receive the correct combination of signals from POM, thus leading to improper optic vesicle/optic stalk regionalization (50).…”

“…The Ap2␣ mutant mouse has defective POM with a reduction of Pitx2 (50). The optic vesicle in the Ap2␣ mutant mouse cannot receive the correct combination of signals from POM, thus leading to improper optic vesicle/optic stalk regionalization (50). In the Smad7 null mice, Pitx2 is down-regulated in the surrounding ocular region, indicating defective patterning of POM.…”