The research work in our laboratory has focused on growth factors that regulate survival and proliferation in the developing nervous system. These regulatory pathways are frequently disrupted in tumor formation or in neurodegeneration.
1. Neurotrophins . During development, target derived neurotrophins promote the survival of presynaptic cells, allowing neurons that are appropriately connected within a neural circuit to survive. This process requires that a signal must be propagated from the nerve terminals along the axon to the nucleus, a distance that can be as large as one meter. Our data indicate that this retrograde signaling requires endocytosis and vesicular transport of receptor-ligand complexes. During retrograde signaling, the endocytosed neurotrophin receptors (Trks) activate the Big MAP kinase pathway (BMK1 or Erk5) leading to nuclear translocation of Erk5 and phosphorylation of the transcription factor CREB. These data establish a unique function for the BMK pathway in signaling from the synapse to the nucleus, and demonstrate that growth factors activate distinct MAP kinase pathways based on the cellular location of stimulation. The location of growth factor release and function could be a general mechanism that allows both specificity and multiplicity of responses to a single growth factor
While target-derived neurotrophins are required for the survival of developing neurons in the peripheral nervous system, the functions of neurotrophins extend well beyond survival. Mice that lack Brain-derived neurotrophic factor (BDNF) are ataxic, indicating that BDNF is needed for cerebellar development and functioning. We have found that BDNF not only promotes the survival of early cerebellar granule cells, but also promotes migration of these cells. We are investigating the signaling mechanisms required for migration, and whether such novel functions of neurotrophins reflect differences in the signaling pathways activated depending on the cellular location of growth factor stimulation.
2 . Modifiers of Sonic Hedgehog . Additional studies focus on the regulation of neuronal precursor proliferation. We have found that proteoglycans and the chemokine SDF modify the ability of Sonic Hedgehog to promote precursor proliferation. We are currently exploring the mechanisms of these effects and the relevance to tumors of the nervous system.
Borghesani PR Peyrin JM, Klein R, Rubin JB, Carter AR, Schwartz PM, Luster A, Corfas G, Segal RA, 2002. BDNF stimulates migration of cerebellar granule cells, Development, 129 :1435-42.
Watson FL , Heerssen HM Lin MZ, Klesse L Bhattacharyya A , Segal RA. 2001 Neurotrophins use the Erk5 pathway to mediate a retrograde survival response Nature Neuroscience 4, 981-988.
Rubin JB. Kung AL , Klein RS, Chan JA, Sung YP, Schmidt K, Kieran MW, Luster AD, Segal RA. 2003. A small molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. PNAS; 100 (23): 13513-8.