Growth Factors in Central Nervous System Development and Oncogenesis
Our lab is interested in mechanisms whereby extracellular stimuli regulate proliferation and survival in the developing nervous system.
In order for target-derived neurotrophins to regulate the survival of a developing presynaptic cell, a signal must be propagated from the nerve terminal along the axon to the nucleus. We found that activated Trk receptors function as rapid retrograde signal carriers to elicit neuclear responses to target derived neurotrophins. Our data indicate that the mechanism of signal propagation is retrograde vesicular transport of activated Trk-ligand complexes. Once they reach the cell body, activated receptors elicit nuclear responses-including phosphorylation of the transcription factor CREB and subsequent induction of the immediate early gene c-fos.
We are currently studying other intermediates required for retrograde signaling and the potential differences in the biological responses to retrograde or local stimulation with growth factors.
Neurotrophins & Cancer
While our studies have highlighted the role of BDNF in normal cerebellar development, we have also demonstrated that neurotrophins, in particular NT3, have a role in cerebellar diseases.
Unregulated growth of cerebellar granule neuronal precursors results in formation of a tumor, known as medulloblastoma. We have found the NT3 receptor TrkC is expressed in these tumors, and that the level of expression is a prognostic indicator for clinical progression. Furthermore, our data show that NT3 induces an apoptotic response in meullobastoma tumor cells, indicating that neurotrophins have potential application in tumor therapy.
While target derived neurotrophins are required for the survival of developing neurons in the peripheral nervous system, the functions of neurotrophins in the central nervous system have been unclear. Mice with a targeted gene deletion of brain-derived neurotrophic factor (BDNF) exhibit a wide based gait, and a defect in cerebellar foliation pattern. At the cellular level cerebellar granule cell survival and migration are both impaired in mutant animals. However, there is an increase in granule cell proliferation in mutants. These data suggest that BDNF acts as an autocrine/paracrine factor to regulate survival, migration, and differentiation of developming CNS neurons, and thereby affects neural patterning.