The transcription factor foxg1 promotes optic fissure closure in the mouse by suppressing wnt8b in the nasal optic stalk

Abstract

During vertebrate eye morphogenesis, a transient fissure forms at its inferior part, known as the optic fissure. This will gradually close, giving rise to a healthy, spherical optic cup. Failure of the optic fissure to close gives rise to an ocular disorder known as coloboma. During this developmental process, Foxg1 is expressed in the optic neuroepithelium, with highest levels of expression in the nasal optic stalk. Foxg1-/- mutant mice have microphthalmic eyes witha large ventralcoloboma.We found Wnt8b expression upregulated in the Foxg1-/- optic stalk and hypothesized that, similar to what is observed in telencephalic development, Foxg1 directs development of the optic neuroepithelium through transcriptional suppression of Wnt8b. To test this, we generated Foxg1-/-;Wnt8b-/-double mutants of either sex and found that the morphologyof the opticcupandstalkandthe closure of the optic fissure were substantially rescued in theseembryos.This rescue correlates with restored Pax2 expression in the anterior tip of the optic fissure. In addition, although we donot find evidence implicating altered proliferation in the rescue,we observe as ignificant increase in apoptotic cell density inFoxg1-/-;Wnt8b-/-double mutantscompared with the Foxg1-/- single mutant. Upregulation ofWnt/β-catenin target molecules in the optic cupandstalkmayunderlie the molecular and morphological defects in the Foxg1-/-mutant. Our results show that proper optic fissure closure relies on Wnt8b suppression by Foxg1 in the nasal optic stalk to maintain balanced apoptosis and Pax2 expression in the nasal and temporal edges of the fissure.