Aldh inhibitor restores auditory function in a mouse model of human deafness

Abstract

Genetic hearing loss is a common health problem with no effective therapy currently available. DFNA15, caused by mutations of the transcription factor POU4F3, is one of the most common forms of autosomal dominant non-syndromic deafness. In this study, we established a novel mouse model of the human DFNA15 deafness, with a Pou4f3 gene mutation (Pou4f3Δ) identical to that found in a familial case of DFNA15. The Pou4f3(Δ/+) mice suffered progressive deafness in a similar manner to the DFNA15 patients. Hair cells in the Pou4f3(Δ/+) cochlea displayed significant stereociliary and mitochondrial pathologies, with apparent loss of outer hair cells. Progression of hearing and outer hair cell loss of the Pou4f3(Δ/+) mice was significantly modified by other genetic and environmental factors. Using Pou4f3(-/+) heterozygous knockout mice, we also showed that DFNA15 is likely caused by haploinsufficiency of the Pou4f3 gene. Importantly, inhibition of retinoic acid signaling by the aldehyde dehydrogenase (Aldh) and retinoic acid receptor inhibitors promoted Pou4f3 expression in the cochlear tissue and suppressed the progression of hearing loss in the mutant mice. These data demonstrate Pou4f3 haploinsufficiency as the main underlying cause of human DFNA15 deafness and highlight the therapeutic potential of Aldh inhibitors for treatment of progressive hearing loss.

Distinguishing Alzheimer’s Disease Patients and Biochemical Phenotype Analysis Using a Novel Serum Profiling Platform: Potential Involvement of the VWF/ADAMTS13 Axis

“…AGAP2 (ArfGAP with GTPase domain, ankyrin repeat and PH domain 2; phosphatidylinositol 3-kinase enhancer—PIKE) was previously assed to have roles in neuron apoptosis and cell death [ 64 ]; here it is implicated in autophagy as well. UPF2 (Up-Frameshift Suppressor 2) is involved in mRNA degradation [ 65 ], and POU4F3 (POU Domain Class 4 Transcription Factor 3) is a transcription factor involved in survival of sensory and motor neurons, apoptosis, and autophagy [ 66 , 67 ]. In the lower right of this figure is a CSMD1 (CUB and Sushi Multiple Domains 1) hub with connections to atherosclerosis phenotypes.…”

High-throughput screening on cochlear organoids identifies VEGFR-MEK-TGFB1 signaling promoting hair cell reprogramming

“…We recently established a novel hair cell fate reporter mouse model by knocking in EGFP-IRES-CreER into the Pou4f3 locus, which allowed hair cell-specific EGFP and CreER expression driven by the endogenous Pou4f3 promoter ( Du et al., 2020 ; Zhu et al., 2020 ). In the heterozygous Pou4f3(EGFP/+) mice, EGFP expression was specifically and robustly detected in hair cells of P0 ( Figure S3 A) and P28 ( Figure S3 B) cochlea, as well as in P0 and P28 utricular hair cells ( Figures S3 C and S3D).…”

“…In the heterozygous Pou4f3(EGFP/+) mice, EGFP expression was specifically and robustly detected in hair cells of P0 ( Figure S3 A) and P28 ( Figure S3 B) cochlea, as well as in P0 and P28 utricular hair cells ( Figures S3 C and S3D). These Pou4f3(EGFP/+) knockin mice did not display auditory dysfunction until at least 3 months age ( Zhu et al., 2020 ) and were suitable for studying hair cell development and lineage specification.…”

“…Rosa2 6-CAG -STOP-Cas9-tdTomato ( Rosa26-tdTomato ) mice were obtained from GemPharmatech, China. Pou4f3-EGFP-IRES-CreER or Pou4f3(EGFP/+) knockin mice were generated using the CRISPR-Cas9 genome-editing technology ( Du et al., 2020 ; Zhu et al., 2020 ). Both male and female mice on a C57BL6 background were used in this study.…”

Cingulin regulates hair cell cuticular plate morphology and is required for hearing in human and mouse

“…We previously generated a Pou4f3 knockin mouse model for DFNA15, another human ADNSHL locus (Vahava et al, 1998), in which the progressive loss of hearing and OHCs is significantly modified by aging, noise exposure, and genetic background (Zhu et al, 2020). The Cgn delG mice in this study also display agedepedentn progressive hearing loss and are more susceptible to noise exposures, reminiscent of the DFNA15 mouse model.…”