# Absence of Ledgf in mouse brain affects the Kmt2a/b and polycomb balance, synaptic transmission and motor function

## TL;DR

This study shows that the absence of LEDGF in mouse brains affects gene regulation, synaptic transmission, and motor function, particularly in the cerebellum.

## Contribution

The study reveals a novel role for LEDGF/p75 in regulating synaptic gene expression via Trithorax in the cerebellum.

## Key findings

- Psip1 cKO mice show motor deficits and altered MeCP2 condensates in cerebellar neurons.
- RNA sequencing shows downregulation of synaptic transmission genes in LEDGF-depleted cerebellum.
- Differentially expressed genes are mainly regulated by Polycomb repressive complex 2 (PRC2).

## Abstract

Lens epithelium-derived growth factor (LEDGF), encoded by the Psip1 gene, exists in two splice variants, LEDGF/p75 and LEDGF/p52. Although little is known about its role in the brain, LEDGF has been proposed to play a role in neurogenesis. Since known LEDGF binding partners, such as PogZ, CDA7L, MLL1 and MeCP2 are implicated in neurological dysfunction, we investigated the role of LEDGF in mouse brain. We developed a conditional Psip1 knock-out (cKO) mouse model by crossbreeding Psip1fl/fl mice with NestinCre mice, resulting in neuronal depletion of both isoforms in the central nervous system. In wild-type (WT) animals, brain region-dependent alternative splicing was evidenced, with more p75 over p52 in the cerebellum and more p52 over p75 in the hippocampus. Behavioral phenotyping revealed that already at a young age, Psip1 cKO mice show motor deficits. In cerebellar neurons, LEDGF depletion results in more and smaller MeCP2 condensates. Bulk and comparative RNA sequencing of cerebellar extracts revealed downregulation of genes involved in synaptic transmission. Moreover, transcription factor network analysis showed that the differentially expressed genes are mainly regulated by the Polycomb repressive complex 2 (PRC2). Since the LEDGF/p75 binding partner MLL1 is part of the Trithorax Complex, the counterpart of PRC2 in gene regulation, our data highlight the importance of LEDGF/p75-mediated regulation of synaptic gene expression in the cerebellum through Trithorax.