Ovadia, S. | bioRxiv Science

bioRxiv2025

Smarcc1 is essential for the patterning of the optic stalk and differentiation of the optic nerve head astrocytes

The optic nerve is essential for vision, and its development depends on the transient neuroectodermal optic stalk, which forms alongside the optic cup through coordinated morphogenesis and differentiation into optic nerve astrocytes that provide lifelong support for retinal ganglion cell (RGC) axons. Here, we delineate key steps in astrocyte formation from the optic stalk and uncover stage- and lineage-specific roles of Smarcc1 (Baf155) and Smarcc2 (Baf170), scaffolding subunits of SWI/SNF chromatin remodeling complexes. Both factors are co-expressed in early retinal pigment epithelium (RPE) and optic stalk progenitors, with Smarcc2 persisting in differentiated derivatives, including RPE and optic nerve astrocytes. Conditional deletion using Dct-Cre revealed reciprocal compensation in pigmented lineages, whereas Smarcc1 loss uniquely caused optic nerve head (ONH) morphogenetic failure, characterized by glial lamina collapse, RGC degeneration, and progressive visual decline. Spatial transcriptomics and functional assays demonstrate that Smarcc1 drives the transition of dorsal optic stalk progenitors from a pigmented, RPE-like state to astrocyte progenitors by repressing pigment gene programs and enabling Pax2/Sox2 activity. After specification, Smarcc1 is required for glial lamina assembly, essential for ONH integrity and RGC survival. These findings establish a mechanism in which Smarcc1-mediated chromatin remodeling couples astrocyte progenitor specification and differentiation with local morphogenesis, ensuring long-term retinal function.

developmental biology↗

bioRxiv2020

Reduced nuclear lamin A/C enhances cancer cell squeezing through rigid barriers, does not facilitate endothelial crossing, and impairs experimental metastasis

The mechanisms by which the nuclear lamina of tumor cells controls their migration and survival are poorly understood. Lamin A and its variant lamin C are key nuclear lamina proteins that control nucleus stiffness and chromatin conformation. Downregulation of lamin A/C levels in two metastatic lines, B16F10 melanoma and E0771 breast carcinoma, facilitated cell squeezing through rigid pores, elevated nuclear deformability and reduced heterochromatin. Unexpectedly, the transendothelial migration of both cancer cells in vitro and in vivo, through lung capillaries, was not elevated by lamin A/C knockdown. Both cancer cells with lamin A/C knockdown grew normally in primary tumors and in vitro on rigid surfaces. Strikingly, however, both lamin A/C deficient melanoma and breast cancer cells grew poorly in 3D spheroids expanded in soft agar cultures. Experimental lung metastasis of both lamin A/C knockdown cells was also markedly reduced. Taken together, our results suggest that high content of lamin A/C in multiple cancer cells promotes cancer cell survival and ability to generate lung metastasis without compromising cancer cell emigration from lung vessels.

cancer biology↗