Journal Club: Zebrafish hair cell generation is regulated by prdm1a

on

Today's journal article

Sandler JE, Tsai YY, Chen S, Sabin L, Lush ME, Sur A, Ellis E, Tran NTT, Cook M, Scott AR, Kniss JS, Farrell JA, Piotrowski T. prdm1a drives a fate switch between hair cells of different mechanosensory organs. 

Why I picked this article

This study is about understanding the molecular "switch" that can change 

Auditory sensory cells in the inner ear are called hair cells. Hair cells exist not only in mammals but also in fish. Fish have hair cells in utricle, saccule and lagna work as both auditory and balance hair cells. In addition, fish also have hair cells in a structure called "lateral line" along the length of their bodies - lateral line hair cells allow fish to sense and coordinate body movement in water. 

In both mammal and fish auditory systems, hair cells are supported by another group of cells called "supporting cells". It's been known for many years that hair cells in fish can regenerate by supporting cells becoming new hair cells. This is in contrast to hair cells in mammals, like humans, which are much harder to regenerate. 

In search of a "switch" that regulates the creation of new hair cells, researchers have searched through their own scientific database (from data collected using a technique called single-cell RNAseq), combined with other datasets provided by other researchers. Researchers have identified a candidate called prdm1a in fish and Prdm1 (Blimp1) in mammals. The current research investigates this gene. 

Some of the research findings

Animal model:

  • Transgenic zebrafish line was used to visualise hair cells, and also with mutations of the target gene prdm1a. 
  • 300microM neomycin was used to ablate hair cells to test regeneration of hair cells.
  • Outcome assessment included, but not limited to:
    • single-cell RNA sequencing
    • ATAC sequencing (assay for transposase-accessible chromatin using sequencing)
    • source imaging data available: http://www.stowers.org/research/publications/libpb-2495.
    • NCBI Gene Expression Omnibus (GEO) database with accession number GSE268538

Findings:

  • prdm1a was found in hair cells of the zebra fish, in both young and old fish. 
  • When there were mutations in the prdm1a gene, hair cells did not get produced at the normal level. The mature fish ended up with fewer hair cells than normal. 
  • The lateral line did not develop very well in prdm1a mutant fish. 
  • Similarly, having mutations in the prdm1a gene reduced regeneration of hair cells in zebra fish. 
  • Molecular profiling suggested that in prdm1a mutant fish, lateral line hair cells shifted to be more like "auditory-hair cell-like". 
  • prdm1a is a type of protein called a "transcription factor" that can regulate the production of proteins based on the genetic blueprint. Researchers showed using DNA-binding assay and genetic manipulation that prdm1a does indeed bind to DNA to regulate other auditory-hair cell genes, and that having more prdm1a results in production of auditory-hair cell proteins, respectively. 
  • The prdm1a mutant fish hair cells change the shape and properties of hair cells. 

Taken together, prdm1a normally reduces the production of auditory-hair cells in fish, and mutations in prdm1a result in switching of lateral line hair cells to be more auditory-hair cell-like. 

Figure 1a. Transgenic zebrafish showing where hair cells are in green, and auditory hair cells are in pink. Sandler et al. (2025)

Haruna's takeaway

Another massive paper and the power of high-throughput sequencing data analysis! It's a nice example of going from a database to identify a possible target and showing the function. It is, however, also a good example that once a candidate is identified from the database, it takes a lot of work to show the potential role for that gene/protein, one gene at a time. The analysis of hair cell shape, like the kinocilium (=the hair part), was very cool. 

If I remember right, the mammalian analogue of the prdm1a gene, blimp1, is a very important regulator for retinal neuron generation, specifically for a type called biopolar cells. The number of "transcription factor" type proteins is limited (~1600 estimated in the genome), and hence, to generate many different types of cells in the body, it seems that a combination of transcription factors is needed to generate a particular cell type. This results in the same transcription factor can have different roles in different organs, and a complex combinations of transcription factors in the right sequence are required to make a particular cell. So the picture is very complicated. But I guess that's the exciting part about this type of development and regeneration research. 

 ------- 

This is Haruna's 24/100 of the 100-day challenge to post a science blog article every day! I love inner ear biology & cochlear physiology.