Rosalind Segal

During development, signaling pathways initiated by extracellular growth factors regulate and coordinate proliferation, differentiation, migration and survival. Understanding growth factor signaling pathways identifies critical steps in development and differentiation of a complex organ system, such as the brain.  Furthermore, targeting growth factor signaling pathways provides a propitious approach to therapy as these pathways exhibit extensive signal amplification and are eminently druggable.  Our research is focused on understanding growth factor pathways critical for normal brain development and functioning, and determining how these pathways contribute to the abnormal proliferation, migration and survival that are key characteristics of brain disorders, particularly brain tumors.

A major proliferative pathway in developing and adult brain is the Hedgehog pathway.  Activation of the Hedgehog pathway drives approximately one third of medulloblastomas, and this pathway can also be activated in astrocytomas.  We identified components of the tumor microenvironment that potentiate proliferative responses to an active SHH pathway, including the chemokine CXCL12 (SDF) and critical heparan sulfate proteoglycans. We demonstrated that these “niche components” are important in normal development and in tumor formation, dissemination and growth, and have explored the implications for new therapies. In recent studies we demonstrated that the SHH pathway is selectively activated in glioblastomas driven by mutations in the gene encoding the PTEN lipid phosphatase. We continue to focus on genetic, biochemical and pharmacologic approaches to define the SHH signaling pathway and to develop new treatments targeting this pathway.

Additional studies address the mechanisms by which the nerve growth factor (NGF) family of neurotrophins promote survival in developing sensory neurons.  Survival and differentiation of sensory neurons in dorsal root ganglia depend on NGF, and the highly related molecules brain-derived neurotrophic factor (BDNF) and neurotrophins 3 and 4 (NT3 and NT4).  These trophic factors are produced by peripheral targets in the skin and muscle.  To understand the spatial aspects of survival signaling we identified gene targets induced by stimulation of receptors on the distal axons, but not by stimulation of receptors on the cell soma.  These studies revealed that the subcellular localization of stimulation provides important information that is transmitted into transcriptional and post-transcriptional regulation. Among these “Retrograde Response Genes” is a bcl2 family member, bcl2l2 or bclw. The bclw-/- mice demonstrate a “dying back neuropathy” associated with an age related loss of peripheral sensation for touch and mechanosensation, and acclerated age-related loss of hearing, indicating that bcl2l2 has a specialized role as an axonal survival signal.  We are now examining the significance of these findings for understanding and treating peripheral neuropathy and hearing loss.