BBS Faculty Member - Rosalind Segal

Rosalind Segal

Department of Neurobiology

Dana Farber Cancer Institute
Smith Building, Room 1058A
450 Brookline Ave.
Boston, MA 02215
Tel: 617-632-4737
Fax: 617-394-2936
Email: rosalind_segal@dfci.harvard.edu
Lab Members: 6 postdoctoral fellows, 3 graduate students, 1 instructor
Visit my lab page here.



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.

In addition, we are using new human and mouse models to address mechanisms of resistance to therapies targeting the SHH pathway.

A second major focus for our laboratory is understanding survival pathways that are critical in development. Our studies address the mechanisms by which neurotrophins, Nerve Growth Factor (NGF) and other family members, promote survival of developing neurons within functional circuitry. Our data have demonstrated spatially selective mechanisms t for survival. We and others have shown that “signaling endosomes” containing activated Trks are transported by dynein motors and signal over prolonged periods of time and prolonged distances. Neurotrophins regulate transcriptional and translational programs during development. Recent work focuses on mechanisms that coordinate transcription, mRNA transport and translation within morphologically complex neurons.

While neurotrophins are required for brain development, they continue to have important roles throughout life. Thus impaired neurotrophin functions contributes to diverse degenerative disorders. We have identified a bcl2 family member that has a specialized role in maintaining axonal viability throughout life. Current studies are focused on the regulation of this anti-apoptotic component, and its distinctive function in preventing axonal degeneration.

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.



Last Update: 6/25/2014



Publications

For a complete listing of publications click here.

 


 

Gruber Filbin M, Dabral SK, Pazyra-Murphy MF, Ramkissoon S, Kung AL, Pak E, Chung J, Theisen MA, Sun Y, Franchetti Y, Sun Y, Shulman DS, Redjal N, Tabak B, Beroukhim R, Wang Q, Zhao J, Dorsch M, Buonamici S, Ligon KL, Kelleher JF, Segal RA. Coordinate activation of Shh and PI3K signaling in PTEN-deficient glioblastoma: new therapeutic opportunities. Nature Medicine, manuscript accepted. Nat Med. 2013 Sep 29. doi: 10.1038/nm.3328. [Epub ahead of print] PMID: 24076665

Witt RM, Hecht ML, Pazyra-Murphy MF, Cohen SM, Noti C, van Kuppevelt TH, Fuller, M, Chan JA, Hopwood JJ, Seeberger PH,
Segal, RA. Heparan Sulfate Proteoglycans Containing a Glypican 5 Core and 2-O-Sulfo-iduronic Acid Function as Sonic Hedgehog Co-receptors to Promote Prolifieration. J. Biol Chem. 2013 Sep 6;288(36):26275-88. Doi: 10.1074/jbc.M112.438937. Epub 2013 July 18. PMID: 2387465

Cosker KE, Pazyra-Murphy MF, Fenstermacher SJ,
Segal RA. Target-derived neurotrophins coordinate transcription and transport of bclw to prevent axonal degeneration. J Neurosci. 2013 33(12):5195-207.

Zhou PC, Alfaro J, Chang EH, Zhao X, Porcionatto M,
Segal RA. Numb links extracellular cues to intracellular polarity machinery to promote chemotaxis. Dev Cell. 2011;20(5):610-22. PMCID: PMC3103748

Chan JA, Balasubramanian S, Witt RM, Nazemi KJ, Choi Y, Pazyra-Murphy, Walsh CO, Thompson M,
Segal RA. Proteoglycan interactions with Sonic Hedgehog specify mitogenic responses. Nat Neurosci. 2009; 12(4):409-17. PMCID: PMC2676236



© 2013 by the President and Fellows of Harvard College