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Tissue boundary formation in the embryonic inner ear: cellular mechanisms and molecular effectors

Reference	BB/L003163/1
Principal Investigator / Supervisor	Dr Nicolas Daudet
Co-Investigators / Co-Supervisors	Dr Vincent Plagnol
Institution	University College London
Department	Ear Institute
Funding type	Research
Value (£)	448,736
Status	Completed
Type	Research Grant
Start date	27/05/2014
End date	29/09/2017
Duration	40 months

Abstract

The emergence and maintenance of sharp boundaries between distinct populations of cells is fundamental for proper tissue morphogenesis and function. The formation of the distinct sensory and the non-sensory regions of the inner ear is one clear example of tissue regionalisation, yet the mechanisms controlling boundary formation in this context are unknown. Using the embryonic mouse and chicken inner ear as model systems, we have found that a functional antagonism between the Notch signalling pathway and the LIM-homeodomain transcription factor Lmx1a could regulate the formation of sensory patch boundaries. In addition, our preliminary data suggest that Lmx1a modulates cell affinity properties, which is one potential mechanism for cell sorting at tissue boundaries. Our next objectives are 1) to determine how the Notch/Lmx1a antagonism impacts on the dynamic behaviour and plasticity of cells at the interface of sensory and non-sensory domains and 2) to use a combination of fluorescence-activated cell sorting, RNA-Seq profiling and ChIP-Seq analysis to uncover the key transcriptional targets and cellular effectors of Lmx1a in the embryonic inner ear. At the end of this project, we will have gained a much deeper and system-level understanding of the cellular and molecular mechanisms of tissue boundary formation in the inner ear. Besides filling an important knowledge gap, this work could lead to the identification of new candidate deafness genes and molecular targets that may be used for gene and stem cell therapies for hearing loss. Because Notch signalling and LIM-homeodomain proteins are evolutionary conserved players in boundary formation, what we learn from their interactions in the inner ear could also help to understand their functions during the morphogenesis of other tissues.

Summary

The very elaborate structure and function of the vertebrate inner ear, containing the sensory organs for hearing and balance, have been shaped by millions of years of evolution. Fish and reptiles have a simple inner ear, which contains a small number of sensory patches and relatively poor hearing capability. In birds and mammals, the increase in number of sensory patches and the accompanying changes in inner ear architecture have led to the acquisition of ever more specialized vestibular and auditory functions. The formation of the inner ear during embryonic life seems to recapitulate this evolutionary history: most of the sensory patches originate from a common 'prosensory' region by progressive segregation. However the signals that control this segregation and establish the spatial boundaries of sensory domains remain mysterious. The aim of this project is to tackle this question in the chicken and mouse embryonic inner ear, using a combination of functional and 'gene discovery' approaches. We will analyse the character and dynamic behaviour of cells during the formation of the boundaries between sensory and non-sensory domains of the inner ear. We will also use new DNA sequencing technologies to unravel the key genetic programs that underlie sensory patch segregation. Besides providing new insights into the mechanisms of formation and evolution of one of our major sense organs, this work could lead to the identification of new genes critical for ear development and function. This is crucial for improving the diagnosis of hereditary forms of deafness and accelerating the development of the 'next-generation' gene and stem cell therapies for hearing loss.

Impact Summary

The immediate beneficiaries from this research will be the basic and biomedical research communities. This project tackles fundamental biological questions relevant to all of our organs and epithelial cells: how do cells differentiate into various cell types and which mechanisms ensure their proper spatial organisation? The answers to these questions are also particularly important for stem cell and biomedical research. For example, this work could lead to the identification of new candidate genes for genetic forms of deafness, and may uncover some of the key molecular signals that regulate sensory and non-sensory cell differentiation in the inner ear. These signals could in turn be used in vitro to promote the differentiation of stem cells into specific inner ear cell types, or in vivo to induce cellular regeneration following inner ear damage. Both strategies are currently envisioned for the future treatment of deafness and age-related hearing loss, which affect an approximate 250 millions people worldwide. Hence additional beneficiaries of our research include charities that support the development of these 'next-generation cures' for deafness (Action on Hearing Loss, Deafness Research UK), the pharmaceutical industry, and hearing loss sufferers. The results of our research will be published in scientific journals with open access policies and presented at international conferences to ensure the widest possible dissemination. The proximity of the UCL Ear Institute with the Royal National Throat, Nose and Ear Hospital will also facilitate knowledge exchange with medical student and ENT medical staff, which could in turn communicate some of the results of our research to their patients. Finally, the Ear Institute hosts regular events with hearing research charities and their supporters, during which we can directly engage with the public and the beneficiaries of our research.

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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