Novel Roles of Sonic Hedgehog Signaling in Retinal Patterning and Neurogenesis During Mammalian Eye Development

Abstract

The Sonic Hedgehog (Shh) signaling pathway is essential for the patterning, growth, and morphogenesis of many tissues. During early eye development, Shh is critical for the formation of the two optic vesicles, which give rise to the retina, retinal pigment epithelium (RPE), and optic stalk. It also regulates the balance between cell proliferation and differentiation during retinal histogenesis, a key process in shaping the cellular architecture of the mature retina. Despite these well-established roles, the temporal dynamics, region-specific functions, and downstream consequences of Shh signaling during retinal development remain poorly understood. Here, we present a comprehensive analysis of Shh signaling across multiple stages of retinal development using temporally and spatially controlled deletion of Smoothened (Smo), an essential transducer of the pathway. This approach reveals previously unrecognized requirements for Shh signaling in specifying optic nerve head identity and maintaining nasal-temporal polarity. We also show that Shh signaling coordinates neurogenesis by sustaining the retinal progenitor pool while also regulating progenitor competence, ensuring appropriate proportions of retinal cell types. Our data indicate that both proliferative capacity and the timing of cell fate specification are shaped by Shh pathway activity. Together, these findings establish new mechanistic links between Shh signaling, regional patterning, and temporal regulation of neurogenesis, providing novel insights into how morphogen signaling is repurposed across developmental time to orchestrate complex tissue architecture.