Biology subjects

Nadar-Ponniah, P. T.

Publications and source records attributed to Nadar-Ponniah, P. T..

3 recordsLinked to original sources

bioRxiv2025

Title: The RNA-binding protein TRIM71 is essential for hearing in humans and mice and regulates the timing of auditory sensory organ development

The RNA-binding protein TRIM71 is essential for brain development, and recent genetic studies in humans have identified TRIM71 as a risk gene for congenital hydrocephaly (CH). Here, we show that mono-allelic missense mutations in TRIM71 are associated with hearing loss (HL) and inner ear aplasia in humans. Utilizing conditional Trim71 knockout mice carrying a CH and HL-associated mutation, we demonstrate that loss of TRIM71 function during early otic development (embryonic day 9-10) causes severe hearing loss. While inner ear morphogenesis occurs normally in Trim71 knockout mice, we find that early otic loss of TRIM71 function disrupts the highly stereotyped timing of cell cycle exit and differentiation within the inner ear auditory sensory organ (cochlea), resulting in the premature formation and innervation of mechano-sensory hair cells. Transcriptomic profiling of Trim71 deficient cochlear progenitor cells identifies Inhba and Tgfbr2 as targets of TRIM71 repression, and our analysis of InhbaTgfbr1 double knockout mice indicates that TRIM71 maintains hair cell progenitors in a proliferative and undifferentiated state by restricting TGF-{beta}-type signaling. Characterization of hair cells and their associated neurons in adult Trim71 knockout mice revealed abnormally short inner hair cell stereocilia, reduced pre-synaptic terminals, and neuronal degeneration in the outer hair cell region, providing a basis for the observed hearing deficits in Trim71 knockout mice.

neuroscience↗

bioRxiv2023

Reactivation of the progenitor gene Trim71 enhances the mitotic and hair cell-forming potential of cochlear supporting cells

Cochlear hair cell loss is a leading cause of deafness in humans. Neighboring supporting cells have some capacity to regenerate hair cells. However, their regenerative potential sharply declines as supporting cells undergo maturation (postnatal day 5 in mice). We recently reported that reactivation of the RNA-binding protein LIN28B restores the hair cell-regenerative potential of P5 cochlear supporting cells. Here, we identify the LIN28B target Trim71 as a novel and equally potent enhancer of supporting cell plasticity. TRIM71 is a critical regulator of stem cell behavior and cell reprogramming, however, its role in cell regeneration is poorly understood. Employing an organoid-based assay, we show that TRIM71 reactivation increases the mitotic and hair cell-forming potential of P5 cochlear supporting cells by facilitating their de-differentiation into progenitor-like cells. Our mechanistic work indicates that TRIM71s RNA-binding activity is essential for such ability, and our transcriptomic analysis identifies gene modules that are linked to TRIM71 and LIN28B-mediated supporting cell reprogramming. Furthermore, our study uncovers that the TRIM71-LIN28B target Hmga2 is essential for supporting cell self-renewal and hair cell formation.

neuroscience↗

bioRxiv2020

Homozygote loss-of-function variants in the human COCH gene underlie hearing loss

Since 1999, the COCH gene encoding cochlin, has been linked to the autosomal dominant non-syndromic hearing loss, DFNA9, with or without vestibular abnormalities. The hearing impairment associated with the variants affecting gene function has been attributed to a dominant-negative effect. Mutant cochlin was seen to accumulate intracellularly, with the formation of aggregates both inside and outside the cells, in contrast to the wild-type cochlin that is normally secreted. While an additional recessive variant in the COCH gene (DFNB110) has recently been reported, the mechanism of the loss-of-function (LOF) effect of the COCH gene product remains unknown. In this study, we used COS7 cell lines to investigate the consequences of a novel homozygous frameshift variant on RNA transcription, and on cochlin translation. Our results indicate a LOF effect of the variant and a major decrease in cochlin translation. This data has a dramatic impact on the accuracy of genetic counseling for both heterozygote and homozygote carriers of LOF variants in COCH.

genetics↗