Grant: Discovery Grants Program - Individual

The long-term goal of my NSERC Discovery research program is to address the fundamental question in the Natural Sciences of how cells receive and respond to signals from their surrounding environment and from neighbouring cells during tissue development. As part of our efforts to fulfill this goal, we have examined molecular mechanisms involved in modulation by growth factor signals and extracellular matrix proteins of embryonic neural crest cells fated to adopt a melanocytic cell lineage. ******In the embryo, neural crest cells constitute a unique, transient and multipotent progenitor cell population with high migratory capacity. These cells differentiate into several lineages, including pigment-producing melanocytes, neurons, glial cells and cardiac cells. A subset of neural crest cells that migrate dorso-laterally from the neural tube towards the ventral abdomen and limbs become melanoblasts. Melanoblasts in turn are progenitor cells that later give rise to postnatal melanocyte stem cells and fully mature melanocytes which produce melanin, and are responsible for animal pigmentation. Our short-term objectives focus on investigating:******1. The mechanisms of melanoblast homing and differentiation in vivo. This objective will determine melanoblast responses to their surrounding environment during migration from the neural crest to ventral regions across the dermis, and the role of ILK in these processes. ******2. The mechanisms of melanogenic responses. This objective will analyze molecular mediators of key melanocyte functions activated by paracrine stimulation from neighbouring cells. ******3. The mechanisms of melanocyte responses to cell-cell interactions. This objective will examine the modulation of melanosome transfer from melanocytes in response to stimuli by neighbouring cells.******We will use genetically engineered reporter mouse models in which we will specifically inactivate the Ilk gene in melanoblasts and their progeny, for lineage-tracing studies in vivo. We will also use primary melanocytic cell cultures to identify at the cellular and molecular level the contribution of various signalling networks to melanocyte survival, differentiation and ability to respond to paracrine stimuli from neighbouring cells. Deciphering the pathways and networks that control responses of melanocytic lineage cells to their surrounding environment and to paracrine signals produced by neighbouring cells will provide key insight into fundamental processes involved in development and function of many essential tissues, including those derived from neural crest cells.*****