Speaker: Tatjana Piotrowski, investigator at Stowers Institute for Medical Research

Title: "Regeneration and evolution of the sensory lateral line system"

Abstract: Hearing loss in mammals is due to the lack of regeneration in the cochlea after the death of mechanosensory hair cells. Regenerating hair cells is a central strategy for restoring hearing, but triggering proliferative regeneration and maturation of hair cells remains elusive. The zebrafish Danio rerio has an array of mechanosensory hair cell-containing neuromasts along the trunk, called the lateral line. Hair cells and surrounding support cells in zebrafish share genetic, functional, and structural similarity with mammalian inner ear hair cells and support cells, but the hair cells of zebrafish readily and rapidly regenerate following death to restore full function. 

Previous studies in our lab have characterized the transcriptional changes in the lateral line in a fine time scale using scRNA-seq, and we identified three core modules that drive the regeneration of hair cells. These three subsequently activated gene modules serve as a blueprint to trigger regeneration in mammals. The transcription factor prdm1a is upregulated in the third module and expressed in hair cells of the lateral line, but not in hair cells of the zebrafish or mammalian inner ear. Previously, prdm1 has been shown to control a fate switch in various cell types, including B lymphocytes and photoreceptors in the retina. We mutated prdm1a in zebrafish and found a drastically reduced number of hair cells and cell proliferation during development and regeneration. We performed scRNA-seq on prdm1a mutants and siblings and discovered a cell type fate switch between lateral line and inner ear hair cells, with many specific inner ear hair cell genes ectopically expressed in lateral line hair cells of the mutants. We performed ATAC-seq and ChIP-seq and identified that Prdm1a binding sites are enriched in the promoters and enhancers of ectopically expressed hair cell genes. Using these enhancers to drive reporters confirms ectopic expression in prdm1a mutants. These findings show that prdm1a plays a crucial role in repressing an inner ear hair cell fate in lateral line organs. Prdm1 might also be a central driver in hair cell type specification and regeneration in other vertebrates. Combined, our data show that Prdm1 is an essential gene to consider in future regeneration attempts in the mammalian cochlea.

Host: GDCB Graduate Student Postdoc Organization