Glial cells were considered, for a long time, to be primarily connective tissue for the nervous system. However, in recent years it has become evident that glia play key active roles in many aspects of nervous system development, function and maintenance. Our laboratory is primarily interested in understanding the molecular mechanisms that mediate the interactions between neurons and glia and in the roles these interactions play in the organism. To this end, we use molecular and cellular biological techniques, as well as genetically modified mice.
The roles of erbB receptor signaling in neuron-glia interactions in the postnatal nervous system in vivo.
Part of our efforts are focused on the growth factor neuregulin (NRG) and its erbB receptors, a signaling pathway that has emerged as a key mediator of neuron-glia interactions. To investigate the roles of this pathway in neuron-glia interactions in the intact nervous system we generated transgenic mice in which erbB signaling in glial cells is blocked by expression of a dominant-negative erbB receptor. Using different glial specific promoters we targeted all macro-glia (astrocytes, Schwann cells, oligodendrocytes) as well as supporting cells of the inner ear, which are similar to glia in several ways. Phenotypic analysis of these mutant lines shows that erbB signaling in glia is critical for the long-term survival of populations of sensory neurons, for the establishment of adequate myelination in the peripheral and central nervous system, for the hormonal control of female puberty. These animal models provide evidence that defects in glia can be the cause of disorders such as neuronal degeneration, deafness and peripheral neuropathies. We are using these model systems to explore further the molecules that mediate neuron-glia interaction and the contributions of glia to neurological diseases. We are also using tissue culture to understand the intracellular mechanisms by which NRG1 regulates Schwann cells.
Mechanisms of radial glia/neural progenitor differentiation and function.
Radial glia are cells that serve as precursors for most neurons and glia in brain and they also provide a scaffold along which most newborn excitatory neurons migrate to their final destination in cortical areas. We are studying the mechanisms that regulate the formation and function of radial glia using cells from the cerebellum and from eth cerebral cortex. Our recent studies show that sequential signaling through the Notch1 and erbB receptors are involved in the regulation radial glia. We are now studying the mechanisms by which there signaling pathways regulate the function and fate of these neural precursors and are identifying new radial glia genes.