For a complete listing of publications click here.
PiN Faculty Member - Rosalind Segal, MD, PhD
Rosalind Segal, MD, PhD
Professor of Neurobiology
Smith Building, Room 1058A
450 Brookline Avenue
Boston, MA 02215
Visit my lab page here.
Proliferative pathways in Brain Development and in 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 glioblastoma and other astrocytomas. We identified components of the tumor microenvironment that potentiate proliferative responses to an active SHH pathway; these include 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. To understand the mechanisms of these important modulators we use biochemical, genetic and cell biology analyses of brain development and of human tumors. Our genetic studies of SHH-proteoglycan interactions demonstrated that proteoglycans specify a proliferative response by localizing Hedgehog ligands to appropriate mitogenic niches, and by altering the time course of Hedgehog pathway activation.
In recent studies we investigated the possibility that the SHH pathway is important for stem cell renewal in astrocytic tumors, and so can synergize with more conventional oncogenic pathways. We demonstrated that the SHH pathway is selectively activated in glioblastomas driven by mutations in the gene encoding the PTEN lipid phosphatase. Therefore Smo inhibitors synergize with inhibitors of PI3 kinase in preventing growth of PTEN-deficient glioblastoma tumor cells, providing a new approach to therapy in this devastating disease. Our findings have led to a clinical trial to treat adults and children with high grade astrocytomas by combining a PI3K inhibitor and a SHH pathway inhibitor that effectively cross the blood-brain barrier.
Survival pathways in Development
During development, target derived growth factors such as Nerve Growth Factor (NGF) regulate the survival of developing neurons. Over many years, this canonical neurotrophin signaling pathway has provided important insights into the mechanisms that regulate survival, apoptosis, and degeneration. Investigating these pathways that regulate cell survival is an important component of my research.
Our studies address the mechanisms by which the nerve growth factor (NGF) family of neurotrophins promote survival in developing neural precursors and in neurons. A major model system that we use is the 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), produced by peripheral targets in the skin and muscle. The target-derived factors function as axon guidance cues to promote axonal elongation and to establish the appropriate circuitry. These same factors also regulate survival of the sensory neurons. Therefore this system provides a wonderful paradigm for identifying the mechanisms that regulate cell survival versus apoptosis.
To analyze the mechanisms by which target derived trophic factors promote survival and prevent apoptosis in sensory neurons, we use both in vivo and in vitro systems. In vivo, we inject NGF or BDNF at the sites of axon terminals, and analyze changes within the sciatic nerve axons. In vitro we use compartmented cultures and microfluidic cultures to recapitulate the separation between the microenvironment surrounding the cell bodies, and the microenvironment that sustains the distal axons. These systems have been valuable in analyzing spatial aspects of survival signaling.
Data from our lab, and from others, demonstrated that “signaling endosomes” containing activated Trks convey signals over prolonged periods of time and prolonged distances. Our studies demonstrated that dynamin-mediated endocytosis of activated receptors and the subsequent dynein-based transport of endosomes containing activated receptors and associated signaling components are necessary for long range signaling. Interestingly we found that endocytosis alters the nature of the response to an extracellular growth factor. Thus, our work demonstrates the importance of receptor endocytosis and duration of signaling for determining the nature of a biological response.
We identified a set of “Retrograde Response Genes” regulated by neurotrophin stimulation only when receptors on distal axons are stimulated and not when receptors on the cell soma are stimulated instead. Thus subcellular localization of stimulation provides important information that is transmitted into transcriptional regulation. One of the Retrograde response genes is the bcl2 family member, bcl2l2 or bclw. This anti-apoptotic family member is evolutionarily more recent than bcl2 itself.
Bclw-/- mice are viable, but exhibit a “dying back neuropathy” together with an age related loss of peripheral sensation for touch and mechanosensation, and accelerated age-related loss of hearing. These data indicate that bcl2l2 has a specialized role as an axonal survival signaling. The bclw mRNA is found both in the cell bodies and in the axons. Thus, local translation of bclw in the axons provides an important mechanism whereby the target derived neurotrophins can promote the survival of a neuron and its complex interconnections.
We use approaches from molecular biology, genetics, cell biology and biochemistry to address questions in neuroscience and neurologic disorders. We use mouse models of human disease, as well as sophisticated culture techniques. Imaging techniques, including real time imaging, in vivo analysis, TIRFF, and confocal microscopy are a major component of our work.
Last Update: 3/25/2015
For a complete listing of publications click here.