RFX2 Compensates for the Loss of RFX1 and RFX3 in the Vestibular System

Authors

• MB Makarious
• M Rizig
• S Bandres-Ciga
• O Ojo
• P Wild Crea
• O Okunoye
• Nigeria Parkinson Disease Research Network International Parkinson's Disease Genomics Consortium - Africa (IPDGC Africa)
• Black and African American Connections to Parkinson‚Äôs Disease (BLAAC PD) Study Group 23andMe Research Team
• M Nalls
• C Blauwendraat
• H Houlden
• A Singleton
• N Okubadejo
• on behalf of the Global Parkinson‚Äôs Genetics Program

Abstract

The group 1 RFX transcription factors (TFs), RFX1, RFX2, and RFX3, are master regulators of ciliogenesis. Our laboratory showed that conditional deletion of Rfx1 and Rfx3 (Rfx1/3;Gfi1-Cre) from mouse hair cells (HCs) results in profound hearing loss, an abrupt loss of all outer HCs shortly after the onset of hearing, and a late mild vestibular phenotype. However, Rfx1/3;Gfi1-Cre mutant HCs have no kinocilia defects. Due to significant homology in functional domains, similar role in ciliogenesis, and expression in cochlear and vestibular HCs, we hypothesized that RFX2 functions to compensate for the loss of RFX1/3 in inner ear HCs. We investigated the compensatory role of RFX2 for RFX1/3 in kinocilia development and maintenance and function in the vestibular system and explored the signaling cascade downstream of the group 1 RFX TFs in vestibular HCs.
A conditional knockout (cKO) mouse of the group 1 RFX TFs (Rfx1/2/3 cKO) underwent vestibular sensory evoked potential (VsEP) testing to measure vestibular function. Rfx1/2/3 cKO mice had significantly elevated VsEP thresholds as early as 1-month-old. Additionally, Rfx1/2/3 cKO kinocilia were shortened in vestibular HCs at postnatal day(P)10 to 6-months-old. Single cell RNA-sequencing of P5 Rfx1/2/3 cKO vestibular HCs identified significantly downregulated genes in Rfx1/2/3 cKO with known ciliogenesis roles. Therefore, RFX2 compensates for RFX1/3 within the vestibular system and the group 1 RFX TFs have an essential role in vestibular function and kinocilia development or maintenance. We reveal part of the group 1 RFX signaling pathway in vestibular HCs, identifying candidate genes for maintaining vestibular function.

Scientific Focus Area: Genetics and Genomics

This page was last updated on Monday, September 25, 2023