DESCRIPTION (provided by applicant): Dendrites are important determinants of neuronal connectivity and the importance of precisely regulating dendritic morphology is suggested by observations that aberrant dendritic growth is associated with neurodevelopmental and neurodegenerative disorders. Currently very little is known about the molecular mechanisms that regulate dendritic morphogenesis. Our goal is to test the central hypothesis that dendritic growth is controlled by regulation of specific genes. We have developed an in vitro model that is uniquely suited to rigorously testing this hypothesis. Rat sympathetic neurons cultured under defined conditions extend a single functional axon, but fail to form dendrites. However, bone morphogenetic proteins (BMPs) trigger these neurons to extend multiple dendrites without altering axon growth or survival. The size of the BMP-induced dendritic arbor is comparable to that of sympathetic neurons in vivo, suggesting that BMPs regulate the full complement of genes necessary for dendritic growth. We propose that isolation of genes differentially expressed in naive vs. BMP-treated sympathetic neurons will enable us to identify candidate genes involved in regulation of primary dendritogenesis. The specific aims of this proposal are to: (1) Identify genes that are differentially regulated in cultured sympathetic neurons during BMP-induced dendritic growth using oligonucleotide microarrays and determine the temporal expression pattern of these genes using quantitative RT-PCR; and (2) Evaluate the functional significance of BMP-regulated genes in dendritic growth by determining if overexpression of BMP-activated genes induces dendritic growth in sympathetic neurons grown in the absence of BMPs, and conversely, if overexpression of down-regulated genes blocks BMP-induced dendritic growth. The relevance of this proposal to the R21 mechanism is that it will generate pilot data establishing the feasibility of a new avenue of research into molecular mechanisms of dendritic growth. It also involves high risk experiments that could lead to a significant breakthrough in understanding of an important question in developmental neurobiology. Since dendritic dysgenesis is associated with neurological disease, defining the molecular mechanisms that regulate dendritic growth will impact our understanding of basic pathogenic mechanisms in the nervous system and provide opportunities for novel preventive/therapeutic approaches.
|Effective start/end date||1/15/04 → 12/31/06|
- National Institutes of Health: $151,023.00
- National Institutes of Health: $163,773.00