Transcriptional Corepressors Panky and Panky-Like Modulate Ganglioside Levels and Are Essential for Retinal Cone...

The biological functions and mechanisms of many cell type-specific transcriptional cofactors remain unclear. We previously identified Panky (Ankrd33) as a repressive transcriptional cofactor that suppresses Crx-mediated transactivation of photoreceptor genes; however, the biological function of Panky remains unclarified. Here, we investigated the functions of Panky and its paralog, Panky-like (Ankrd33b), in mice of either sex. Single knock-out (KO) mouse retinas of Panky or Panky-like did not show significant alterations at both histological and functional levels compared with those of control mice. We then established and examined Panky and Panky-like double knock-out (PPL DKO) mice. PPL DKO mice exhibited decreased light-evoked activities detected by electroretinogram (ERG), impaired cone photoreceptor morphology revealed by immunohistochemistry, and structural deformity of cone outer segments and synaptic terminals indicated by transmission electron microscopy, followed by cone death at a later stage. Lipidomics analysis revealed elevated ganglioside levels in PPL DKO retinas, consistent with the increased immunoreactivity of GT1b and GD3 in the outer segment layer. RNA-seq analysis was conducted in a cone-enriched context resulting from Nrl deficiency and showed that the Cerkl gene, whose mutations in humans cause retinitis pigmentosa (RP26), was upregulated in Panky/Panky-like/Nrl triple KO mice. Transcriptional assays showed that PPL suppressed Crx-mediated transactivation of Cerkl In addition, AAV-mediated Cerkl overexpression in the mouse retina induced significant photoreceptor cell death. Taken together, these findings suggest that the repressive Panky and Panky-like cofactors, which modulate Crx transcriptional activities and thus ganglioside levels in the mouse retina, are essential for cone photoreceptor structure and maintenance.