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Regulation of ventral otic patterning and integration with general programmes of neurogenesis in the zebrafish embryo

Final Report Summary - EM ZF OTIC 082010 (Regulation of ventral otic patterning and integration with general programmes of neurogenesis in the zebrafish embryo)

The vertebrate inner ear is a complex three-dimensional structure with hearing and balancing functions. Sensory hair cells, neurons of the inner ear ganglion, and the structural cells of the auditory and vestibular system of the inner ear all arise during embryonic development from the otic placode. To form a functioning organ it is crucial that the right cells form at the right time in the right place. In our project we investigated patterning and maintenance events during zebrafish inner ear development to gain insights into how all these cell types arise and what interactions occur along the way. We have identified a critical time point for pattern refinement and maintenance and we have gained evidence that otx1 is a key factor for non-neurogenic otic development. In addition, we could show that Fibroblast Growth Factor (FGF) and retinoic acid (RA) signalling play critical roles in intra-otic patterning. Perturbing either of these signalling pathways leads to malformed inner ears. Interestingly we find that not only FGF as previously described but also RA signalling factors regulate the emergence of otic neuroblasts from the otic placode and are required for sensory cell formation, providing new insights into the function of RA signalling during the early stages of otic development. Moreover, our data suggests that FGF and RA are interconnected in a feedback loop. This places RA and FGF signalling in the otic tissue itself at the heart of an inter-regulatory loop that ensures correct patterning is maintained.

Investigating the in vivo signalling events leading to cell specification and differentiation in the inner ear is crucial for our understanding of the complicated relationships between signalling molecules and cell fate choices. During development, only a few signalling pathways are employed over and over again to pattern all of the emerging adult tissues. This suggest that timing and context of a given signal are an important component of the signal outcome. In the field of inner ear research, major efforts are made to mimic the in vivo specification events in culture, growing inner ear hair cells and otic neurons for replacement therapies in deaf patients. Both FGF and RA signalling are employed in this context, but the amount of desired cells (hair cells or neurons) that are obtained in culture is relatively low and often variable. Our study highlights that RA and FGF signalling critically depends on their time of action. In addition, inter-regulatory feedback mechanisms, in addition to specificity of a given FGF molecule (FGF3 versus FGF8) all contribute to a better understanding of inner ear cell specification, an understanding that can help to improve in vitro culture methods and thus impact on patient health.