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
Lab Members: 4 postdoctoral fellows, 2 graduate students
Visit my lab page here.

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.

Last Update: 7/29/2015


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

Zhao X, Ponomaryov T, Ornell KJ, Zhou P, Dabral SK, Pak E, Li W, Atwood SX, Whitson RJ, Chang AL, Li J, Oro AE, Chan JA, Kelleher JF,
Segal RA. RAS/MAPK activation drives resistance to Smo inhibition, metastasis and tumor evolution in Shh pathway-dependent tumors. Cancer Res. 2015 Jun 30. pii: canres.2999.2014. PMID:26130651

Eisner A, Pazyra-Murphy MF, Durresi E, Zhou P, Zhao X, Chadwick EC, Xu PX, Hillman RT, Scott MP, Greenberg ME,
Segal RA. The Eya1 phosphatase promotes Shh signaling during hindbrain development and oncogenesis. Dev Cell. 2015 Apr 6;33(1):22-35. doi: 10.1016/j.devcel.2015.01.033. Epub 2015 Mar 26. PMID:25816987

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