PgmNr Z617: Cell proliferation and differentiation are controlled by different Fgf downstream targets during sensory hair cell regeneration.

Authors:
Mark E. Lush; Scott Freeburg; Tatjana Piotrowski


Institutes
Stowers Institute for Medical Research, Kansas City, MO.


Abstract:

Organ regeneration is a complex process involving integration of multiple cell signaling pathways. The zebrafish lateral line contains mechanosensory hair cells that respond to vibrations in the surrounding water and serve as a great model to study the development and regeneration of the auditory system. Lateral line hair cells are surrounded by at least two groups of support cells, which together form a structure called the neuromast. Unlike mammals, the sensory hair cells of the lateral line regenerate after damage. We have previously shown that hair cell regeneration requires Notch down regulation and Wnt-dependent proliferation of a resident support cell population. Other signaling pathways, such as Fgf are also expressed in mature neuromasts. Fgf signaling is required for lateral line development, as it is for the ear of mouse, chicken and zebrafish, but its role in regeneration has not been studied. RNASeq and in situ hybridization analyses show that fgf3 and fgf10a, and the receptors fgfr1a and fgfr2 are expressed in naïve neuromasts and are immediately down regulated after hair cell death. This finding suggests that down regulation of Fgf signaling maybe required to initiate hair cell regeneration. Indeed, in fgf3 mutants, hair cell regeneration is enhanced due to increased support cell proliferation. This finding is significant, as it suggests that Fgf3 manipulations might be important for inducing regeneration in the mammalian ear. Interestingly, fgf10a mutants do not show differences in regeneration potential, suggesting that different fgf ligands may activate different receptors or downstream signaling pathways in the lateral line. Increased hair cell regeneration and proliferation is mimicked by low dose treatment with pharmacological inhibitors of Fgf receptors. Surprisingly, high doses of Fgf inhibitors block regeneration, even though proliferation is still increased. These findings suggest that proliferation and hair cell differentiation are regulated via different receptors or downstream targets. Inhibition of Notch signaling during regeneration also leads to increased cell proliferation suggesting that Notch and Fgf might interact. However, Notch inhibition and the fgf3 mutation affect different downstream genes. Also, in fgf3 mutants or after inhibition of Fgf signaling, proliferation is even increased in undamaged neuromasts, which is not the case after Notch inhibition. These results show that Notch and fgf3 initiate divergent downstream signaling events to inhibit proliferation during homeostasis and regeneration. Therefore, the combined downregulation of these pathways should be explored in mammals to trigger proliferation and regeneration.



ZFIN Genetics Index
1. fgf3
2. fgf10a
3. fgfr1a
4. fgfr2