Exploring a novel role of neural crest during otic vesicle morphogenesis

The inner ear contains sensory epithelia that detect head movements, gravity and sound. Only recently some researchers have reached a moderate success in developing sensory epithelia from pluripotent stem cells by culturing inner ear stem cells in a 3D environment. It has been assumed that a 3D environment can mimic some of the properties present during normal embryo develop and that are required for stem cell establishment and proper differentiation. During normal development the inner ear is formed from a flat piece of tissue that is transformed by unknown mechanisms into a ball of cells with an internal cavity, called otic vesicle. Later this otic vesicle will give rise to all derivatives of the inner ear. The aim of this project is to generate a cellular, molecular and biomechanical explanation of how the otic vesicle is formed during normal development. In addition we will use this information to generate otic vesicles in vitro, which will allow understanding the intimate details of this complex morphogenetic process. This project will lay the foundations for future research concerning the generation of inner ear stem cells in vitro, essential for modelling inner ear disorders or developing cell-based therapies for profound hearing loss and balance disorders.

Morphogenesis is a fundamental aspect of developmental biology, essential for early development and organ formation. A common morphogenetic process is cavity formation, which occurs by invagination (e.g. mammalian neurulation) or cavitation (e.g mammalian blastulation). However, the mechanism that controls cavity formation is poorly understood. In this project we will use the formation of the otic vesicle as an example of cavity morphogenesis, which happens by either invagination (amniotes) or by cavitation (Xenopus). The otic vesicle together with some neural crest cells give rise to the inner ear, a complex organ responsible of detecting head movements and sound. We will test the novel idea that otic vesicle formation is dependent on its interaction with neural crest cells.

Most of the experiments on otic vesicle cavitation will be performed in Xenopus embryo because this animal model offers several advantages for this project (large cells, ease of manipulation, and robust ex vivo culture). We will then compare our results with otic vesicle formation in chicken embryos, an example of invagination. We will test the role of neural crest on otic vesicle morphogenesis by blocking neural crest induction/migration and analysing otic vesicle formation. High-resolution live imaging and analysis of forces of placode cells will be performed to characterize the cellular behaviours during otic vesicle formation and determine how neural crest cells control these. We will perform loss of function experiments of candidate molecules that could be necessary for neural crest-placode communication, followed by analysis of otic vesicle formation. A computational model for otic vesicle formation will be generated and its predictions tested in vivo. We will use the knowledge obtained in this project to produce otic vesicles in vitro, an essential step for developing sensory epith

In this collaborative multi-disciplined project, we identify the international science base, the general public and the biotech industry as beneficiaries beyond the immediate academic community. Expert training of the appointees will contribute directly to the science base. We aim to identify the mechanism by which otic vesicle forms during normal development. This will allow generating otic vesicles in vitro, an essential step to generate otic stem cells. Stem cell and in vitro organogenesis will directly benefit the biotech industry. To achieve maximal impact of the research, we will provide a broad range of scientific training through the combination of internationally recognized expertise bought by the applicants. In addition, professional training will be ensured through the infrastructure provided by the world-class universities in which the research will be performed. We will engage the public through the UCL facilities to communicate and disseminate our discoveries to the general public. In addition to interactions with the general media, lay publications and outreach activities aimed at school children. We are currently interacting with a private company to develop video games based on movement of cells that could relate to the general public. We will continue with this kind of activities to ensure that our research will provide major impact in several disparate areas.