MECHANISMS OF TRANSCRIPTION FACTOR DISTRIBUTION IN CEREBROSPINAL FLUID LENDING INSIGHT INTO MOOD DISORDERS

OTX2 transcription factor is required for choroid plexus (ChP) development, and its expression is maintained in adulthood within ChP epithelial cells. While most OTX2 exerts its activity in the ChP, a small fraction is continuously secreted into the CSF and transferred to cortical interneurons, where it regulates critical period plasticity. Alterations in this ChP–CSF–cortex pathway have been linked to anxiety-like phenotypes in mouse models of early-life stress. However, the transcriptional activity of OTX2 in the adult ChP, its molecular partners, and the impact of developmental disruptions on this signaling remain poorly understood. We aim to address these fundamental questions in the adult mouse ChP. OTX2 transcriptional targets were identified using CUT&RUN in ChP nuclei to define its regulatory networks. In parallel, proximity-based proteomics using TurboID was employed to identify OTX2 protein partners involved in its nuclear functions and secretion pathway. Finally, a maternal immune activation (MIA) model will be used to assess whether developmental stress alters OTX2 activity and/or signaling.
Preliminary results reveal extensive transcriptional activity of OTX2 in the adult ChP, including regulation of Wnt signaling components, a pathway also controlled during development. As the ChP hosts the earliest circadian clock in the brain, OTX2 regulates key circadian genes, notably Bmal1. Initial analysis of proteomics data suggest interactions with chromatin remodeling complexes, and proteins involved in non-conventional secretion pathways. Further biochemical and functional validations are required to confirm these findings and fully define OTX2 functions in the adult ChP.