Smarcc1 drives optic stalk patterning and optic nerve head astrocyte differentiation

ABSTRACT

The optic nerve develops from the neuroectodermal optic stalk, which undergoes coordinated morphogenesis and gives rise to optic nerve astrocytes that support retinal ganglion cell axons. Here, we define the progression of astrocyte formation from the optic stalk and identify stage-specific functions of the SWI/SNF scaffolding subunits Smarcc1 and Smarcc2. Both factors are co-expressed in retinal pigment epithelium (RPE) and optic stalk progenitors, with Smarcc2 persisting in differentiated RPE and astrocytes. Conditional deletion using Dct-Cre revealed compensatory activity in pigmented lineages, whereas Smarcc1 loss uniquely disrupted optic nerve head morphogenesis, resulting in glial lamina collapse, retinal ganglion cell degeneration and progressive visual decline. Spatial transcriptomics and functional assays show that Smarcc1 enables dorsal optic stalk progenitors to transition from a pigmented, RPE-like state to astrocyte progenitors by repressing pigment gene programs and permitting Pax2 and Sox2 activity. After specification, Smarcc1 is also required for glial lamina assembly and astrocyte migration into the inner retina. These findings demonstrate that Smarcc1-dependent chromatin remodeling coordinates astrocyte specification with optic nerve head morphogenesis to maintain long-term retinal function.