Asxl1 regulates optic cup development through interaction with Lhx2 and epigenetic modulation of Wnt signaling.

The () gene is a chromatin regulator involved in transcriptional activation and repression. While Asxl1 plays a crucial role in various organ development, its role in ocular development remains unclear. Here, we analyzed knockout (KO) mice and observed disrupted optic cup formation at embryonic day 10.5 (E10.5). RNA-seq of the E10.5 optic cup revealed dysregulation of Wnt signaling and early eye development genes. In further investigation using isolated cell from E10.5 retinal region, neuroepithelial stem cells from KO embryos exhibited impaired proliferation and spheroid formation. To elucidate the transcriptional mechanism by Asxl1 in optic cup formation, biochemical assays demonstrated that Asxl1 binds the LIM domain of Lhx2, facilitating repression of Wnt1, Wnt2, and Wnt8b. Following ChIP analysis showed that the gain of function of Asxl1 increased repressive histone marks (H3K27me3, H3K9me3) and reduced active marks (H3K4me3) at Lhx2-binding motifs within the cis-regulatory regions of canonical Wnt ligand genes. These findings establish Asxl1 as a key epigenetic regulator of optic cup development by modulating Lhx2-mediated Wnt signaling, providing insights into congenital eye disorders.