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Research unit director
Cell replacement therapy is a promising avenue for treating neurodegeneration. In the retina, recent clinical trials and work in mouse models raised the hope that such therapies might become a reality in the clinic for retinal degenerative diseases. A major hurdle of these approaches, however, is the difficulty to induce specific and efficient photoreceptor cell differentiation from stem cells, highlighting the importance to advance knowledge in the basic mechanisms regulating retinal cell type specification. Despite some exciting results with cell transplantation in mouse models of retinal degenerations, major drawbacks remain, such as: 1) The efficiency of photoreceptor generation from stem cells is low; and 2) grafted cells poorly integrate the host tissue. To overcome these challenges, it is essential to acquire a deep understanding of how retinal progenitor cells (RPCs) give rise to different retinal cell types, and how photoreceptors migrate to their position and acquire their highly polarized morphology during retinogenesis. Our research program contain multiple projects coherently organized to address three major questions:

1) How are neural progenitor cell lineages shaped?
Mechanisms controlling the mode of division, symmetric or asymmetric, ultimately determine tissue size and cellular composition, but the molecular mechanisms remain poorly understood in vertebrates. We use mouse genetics and live imaging to study how RPCs divide symmetrically or asymmetrically, and whether manipulating this process can improve stem cell differentiation protocols.

2) How do neural progenitor cells change over time?
The various retinal cell types are generated at different stages during development from the same pool of multipotent RPCs. How exactly RPCs change their temporal identity to alter fate output as development proceeds remains unclear. Our recent work identified a transcriptional cascade potentially controlling temporal identity in RPCs, but the mechanisms at play are unknown. We use large-scale genomic and proteomic approaches to identify the targets and interacting partners of the cascade and how they operate to control temporal identity.

3) How do sensory cells polarize and integrate in their appropriate layer?
How photoreceptor cells end up in the appropriate layer and establish the polarized morphology necessary for light detection remains unclear, but elucidating these mechanisms will be crucial to improving integration of grafted cells into the host retina. We work on novel mechanisms that appear to control photoreceptor cell positioning and polarity and test whether manipulating these pathways can improve cell integration after grafting.

Our ultimate goal is to use the knowledge generated from addressing these fundamental questions to improve cell transplantation approaches for retinal degenerations. Since the retina is part of the central nervous system, we expect that this work will also have impact on the development of cell-based therapies for neurodegenerative diseases affecting other regions of the central nervous system.

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