Journal Club: TRIM71, a gene linked to hydrocephalus, is also linked to some hearing loss via altered development.

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Today's journal article

Li XJ, Morgan C, Duy PQ, Evsen L, Hao LT, Machavoine R, Belhous K, Ernest S, Denoyelle F, Mignot C, Brioude F, Parodi M, Li L, Huang H, Nadar Ponniah PT, Kolanus W, Kahle KT, Marlin S, Doetzlhofer A. The RNA-binding protein TRIM71 is essential for hearing in humans and mice and times auditory sensory organ development. 

Why I picked this article

This study explores the role of TRIM71, a type of protein that binds to RNA, in the development of the cochlea and familial hearing loss. 

The inner ear’s sensory organ (cochlea) is made of hair cells, supporting cells, and spiral ganglion neurons, all arising through tightly controlled developmental timing. During development, progenitor cells (= cells that can still become different types of cells, and are dividing) continue to divide until they stop cell division and choose their path to become a certain type of cell. The process is highly regulated to ensure the correct number of each cell type is made in the cochlea. 

TRIM71 is a gene already known as a gene important for brain development, and is also a gene linked to hydrocephalus. TRIM71 is thought to be important to maintain the premature state of progenitor cells, and impairment in TRIM71 function can lead to abnormal development. 

Some of the research findings

Clinical finding: 

  • Some patients with variation in TRIM71 reported hearing loss. Those patients with hearing loss were identified and underwent more testing. Some were identified with hearing loss and abnormalities in ear anatomy.

Are TRIM71 found in the cochlea?:

  • Published single-cell RNAseq database were analysed - TRIM71 appear to be found in the various parts of the ear from very early development. 
  • Using a mouse model and RNA or protein detection methodology, researchers found signs of TRIM71 in the otic vesicle (an early structure which will later become the ear). 

Transgenic animal study:

  • To explore this, the researchers generated Trim71 conditional knockout mice with a mutation matching that found in CH and HL patients. 
  • Deleting Trim71 specifically during early inner ear development (E9–E10) caused severe hearing loss, despite normal cochlear shape.
  • To further test the hypothesis that Trim71 is important in controlling the cochlear progenitor cells, researchers examined the marker for progenitor cells (cell division). In Trim71-deficient mice, hair cell progenitors exited the cell cycle too early, forming hair cells prematurely. 
  • These early-born hair cells were abnormally innervated and later showed synaptic reduction and neuronal degeneration, especially in the outer hair cell region.
  • Trim71 is likely to play a role in the cochlea by regulating another protein/gene. To find some candidate, researchers used the transcriptome analysis comparing the Trim71-deficient cochlea and the control. 
  • RNA sequencing of cochlear progenitor cells lacking Trim71 revealed upregulation of TGFβ pathway genes, including Inhba and Tgfbr2. This is a very important known pathway for regulating cell cycle. 
  • Follow-up experiments in Inhba-Tgfbr1 double knockout mice show more proliferation in the cochlea, suggesting a delay in cell cycle exit.

This suggest that TRIM71 normally acts to suppress TGFβ signaling, helping progenitors stay in a proliferative, undifferentiated state during a critical time window.

From part of Fig3E. Pink color shows hair cells, green show dividing cells (still have progenitor-like property). Li et al. 2025

Haruna's takeaway

The overlap between hydrocephalus and hearing loss via the role of the common gene, TRIM71, is a reminder that many genes have roles in different organs. It appears that TRIM71 governs stemness and progenitor cells becoming mature cells in multiple organs. 

This research was a type of work where the observation of hearing loss in a particular human clinical population (in this case, hydrocephalus patients with a genetic factor) then led to pursuing the mechanism of the disease using mice. I like this type of approach. It's a nice approach as the human clinical relevance is at the forefront. The hearing loss in the human population with TRIM71 variants seemed to be very variable, highlighting the complexity of understanding how a change in one gene can still manifest into different phenotypes. 

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This is Haruna's 39/100 of the 100-day challenge to post a science blog article every day! I love inner ear biology & cochlear physiology.