Setd5, but not Setd2, is indispensable for retinal cell survival and proliferation

Abstract

Trimethylation of histone H3 at lysine 36 (H3K36me3) is associated with active transcription. We used mouse retinal explant cultures and shRNA to investigate the roles of Setd2 and Setd5, which encode H3K36me3 methyltransferases, in retinal development. We found that shSetd5 caused abnormal retinal structures and reduced rods and M€ uller cells, whereas shSetd2 did not cause any abnormalities. The mutant SETD5 lacking the SET domain failed to reverse the phenotypes observed in the shSetd5-expressing retinas, while SETD5S1257*, which does not interact with HDAC3 and PAF1 complexes, rescued proliferation, but not apoptosis, induced by shSetd5. Taken together, we found that Set-d5, but not Setd2, is essential for sustaining retinal cell survival and proliferation, and the SET domain of SETD5 is pivotal for both functions.

CRISPR/Cas9-Induced Inactivation of the Autism-Risk Gene setd5 Leads to Social Impairments in Zebrafish

“…In addition, we observed that setd5 heterozygous embryos show a reduced body length compared to setd5+/+ ones, while the ratio between eye size and body length indicates that they would be affected by microphthalmia. This is very similar to the morphological phenotype described for zebrafish embryos injected with setd5 morpholino and heterozygous mouse Setd5 mutants [15,16,31]. It also represents a common clinical feature of individuals affected by human 3p25.3 microdeletion syndrome, in which one copy of SETD5 is entirely deleted [9], further supporting the idea that the zebrafish setd5 mutants carry a LoF mutation.…”

“…A group of 4 fishes was placed in the novel tank and recorded for 10 min without adaptation. Video recordings were analyzed by Zebralab software (ViewPoint, Civrieux, France) to calculate the mean speed of the shoal, shoal polarization, Inter-Individual Distance (IID) and Nearest Neighbor Distance (NND) [31,32].…”