Rosalind Segal

Department of Neurobiology
Dana-Farber Cancer Institute

Departments of Cancer Biology and Pediatric Oncology
Smith Building, Room 1058A

450 Brookline Ave.
Boston, MA 02215
Tel: (617) 632-4737
Fax: (617) 632-2085
Email: Rosalind_segal@dfci.harvard.edu

Web Page: The Segal Lab Page
6 postdoctoral fellows, 3 graduate students, 1 instructor

Our laboratory investigates the process of neural development – how the nervous system develops from neural stem cells to neurons that function within a neural circuit. We focus on the extracellular cues, such as growth factors and morphogens that direct this complex process. Neural stem cells are self-renewing precursors capable of giving rise to additional stem cells and to differentiated neurons and glial cells. A feature of the specialized niches where stem cells are found in the developing and mature brain is that they contain both critical protein growth factors and specialized proteoglycans. Sonic Hedgehog (Shh) is one such growth factor. We are studying the mechanisms by which Shh regulates neural stem/precursor proliferation in the cerebellar cortex, and other mitogenic niches. Using genetic approaches to disrupt the binding of Shh to proteoglycans, we find that Shh interactions with specialized proteoglycans are needed for a proliferative response to Shh. As mutations that activate the Shh signaling pathway cause brain tumors and other cancers, Shh-proteoglycan interactions are likely to be important in oncogenesis. We are currently investigating the ways in which inhibitors of Shh signaling might be used in treating brain tumors that arise from neural stem/precursors.

The migration of neural precursor cells away from the mitogenic stem cell niche enables the cells to exit the cell cycle, and differentiate. However brain tumor cells have the ability to both divide and migrate. Our studies have identified brain-derived neurotrophic factor (BDNF) as a critical chemotactic factor for neural precursors. We are using both in vivo and in vitro approaches to determine how precursors or tumor cells perceive and respond to a gradient, and migrate through the brain parenchyma.

When differentiated neurons reach their destinations they form synapses and become incorporated into functional circuits. Neurons that form connections survive due to the actions of neurotrophins, while neurons that fail to connect undergo apoptosis. We are interested in understanding how neurotrophins allow the selective survival of neurons that are part of a circuit. We have found that neurotrophin receptors must be activated, internalized, and transported by a dynein motor in order to transmit a survival signal from the synapse to the nucleus. These studies will help identify new signaling pathways that can be exploited to treat neurodegenerative disorders such as Amyotrophic Lateral Sclerosis and progressive sensory neuropathy.

References:

Rubin JB, Kung AL, Klein RS, Chan JA, Sung Y, Schmidt K, Kieran MW, Luster AD, Segal RA. A small molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13513-8.
Zhou P, Porcionatto M, Pilapil M, Chen Y, Choi Y, Tolias KF, Bikoff JB, Hong EJ, Greenberg ME, Segal RA. Polarized signaling endosomes coordinate BDNF-induced chemotaxis of cerebellar precursors. Neuron. 2007 Jul 5;55(1):53-68.
Chan JA, Balasubramanian S, Witt RM, Nazemi KJ, Choi Y, Pazyra-Murphy MF, Walsh CO, Thompson M, Segal RA. Proteoglycan interactions with Sonic Hedgehog specify mitogenic responses. Nat Neurosci. 2009 Apr;12(4):409-17.
Pazyra-Murphy MF, Hans A, Courchesne SL, Karch C, Cosker KE, Heerssen HM, Watson FL, Kim T, Greenberg ME, Segal RA. A retrograde neuronal survival response: target-derived neurotrophins regulate MEF2D and bcl-w. J Neurosci. 2009 May 20;29(20):6700-9.

BBS webpage updated 6/14/2010