Six3acts independently ofPax6to provide an essential contribution to lens development

Abstract

ABSTRACTThe Six3 transcription factor is essential for forebrain and eye development, andSIX3mutations cause the congenital disorder holoprosencephaly. We created asix3mutant inXenopus tropicaliswith a mild holoprosencephaly phenotype, and unlike mouseSix3mutants that are headless/eyeless, theXenopusmutant forms some eye structures, allowing direct study of Six3 function in eye formation. We focus here on striking deficits in lens formation. Early lens induction occurs normally in the mutant, e.g., the essential eye genepax6, is activated in lens ectoderm, persisting in the eye to a late developmental stage, but in many embryos the lens fails to form. We found thatbmp4, bmp7.1, smad7, dll1, dlc, mab21l1and/ormab21l2, previously unknown assix3eye targets, are downregulated in the mutant. We show thatsix3is required for lens formation, acting primarily in developing retina during neurulation through BMP and Notch signaling, and thatmab21l1/mab21l2regulate(s) this BMP activity. This work reveals previously unrecognized essential roles forsix3in eye development, identifying its key role in signaling needed for lens formation, and acting independently ofpax6activity.SUMMARY STATEMENTThis study identifies thesix3transcription factor as the mediator of key inductive signals driving lens formation, acting independently ofpax6in early phases of lens formation.