Neurobiology

Rosalind Segal, M.D., Ph.D.

Professor of Neurobiology
Harvard Medical School
Department of Pediatric Oncology
Dana-Farber Cancer Institute

Our lab is interested in mechanisms whereby extracellular stimuli regulate proliferation and survival in the developing nervous system.

Neurotrophin Signaling

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.

Cerebellar Development

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.