Photo of Rosalind A. Segal,  MD, PhD

Rosalind A. Segal, MD, PhD

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute
Phone: (617) 632-4737
Fax: (617) 632-2085

Rosalind A. Segal, MD, PhD

Dana-Farber Cancer Institute


  • Professor, Neurobiology, Harvard Medical School
  • Professor of Neurobiology, Ted Williams Senior Investigator, Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute


Research Abstract

The research work in our laboratory has focused on growth factor signaling pathways that regulate survival, proliferation and migration in the developing nervous system. These pathways are normally exquisitely regulated; disruption of these pathways can result in brain tumors or neurodegenerative disorders.

Survival. During development, target derived neurotrophins promote the survival of presynapic cells, allowing neurons that are connected within a neural circuit to survive. Our studies investigate this long distance signaling. Our studies have identified a specialized gene expression program, the retrograde response genes, that prevent axonal degeneration. We use molecular imaging approacher to determine how transcripting and local ...of retrograde response genes are regulated.

Proliferation and migration. We have found that factors that contribute to the proliferation and migration of neural precursors in the developing brain also are responsible for the abnormal proliferation and migration of brain tumor cells. We have identified mechanisms whereby heparan sulgate proteoglycans and chemokines modulate SHH signaling and contribute to proliferation. Our studies focus on how these processes are regulated in normal development, and how this regulation is lost in cancers.



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  • 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. PubMed
  • 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; 33:22-35. PubMed
  • Persson L, Witt RM, Galligan M, Greer PL, Eisner A, Pazyra-Murphy MF, Datta SR, Segal RA. Shh-proteoglycan interactions regulate maturation of olfactory glomerular circuitry. Dev Neurobiol 2014. PubMed
  • Bergthold G, Bandopadhayay P, Bi WL, Ramkissoon L, Stiles C, Segal RA, Beroukhim R, Ligon KL, Grill J, Kieran MW. Pediatric low-grade gliomas: How modern biology reshapes the clinical field. Biochim Biophys Acta 2014; 1845:294-307. PubMed
  • Cosker KE, Segal RA. Neuronal signaling through endocytosis. Cold Spring Harb Perspect Biol 2014. PubMed
  • 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. Nat Med 2013; 19:1518-23. PubMed
  • 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 proliferation. J Biol Chem 2013; 288:26275-88. PubMed
  • 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; 33:5195-207. PubMed
  • Courchesne SL, Karch C, Pazyra-Murphy MF, Segal RA. Sensory neuropathy attributable to loss of Bcl-w. J Neurosci 2011; 31:1624-34. PubMed
  • Courchesne SL, Pazyra-Murphy MF, Lee DJ, Segal RA. Neuromuscular junction defects in mice with mutation of dynein heavy chain 1. PLoS ONE 2011; 6:e16753. PubMed
  • Cosker KE, Segal RA. The longer U(T)R, the further you go. Nat Neurosci 2010; 13:273-5. PubMed
  • Gruber-Olipitz M, Segal RA. Live or let die: CCM2 provides the link. Neuron 2009; 63:559-60. PubMed
  • 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; 29:6700-9. PubMed
  • Arimura N,Kimura T,Nakamuta S,Taya S,Funahashi Y,Hattori A,Shimada A,Menager C,Kawabata S,Fujii K,Iwamatsu A,Segal RA,Fukuda M,Kaibuchi K. Anterograde transport of TrkB in axons is mediated by direct interaction with Slp1 and Rab27. Dev Cell 2009; 16:675-86. PubMed
  • 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; 12:409-17. PubMed
  • Ha J,Lo KW,Myers KR,Carr TM,Humsi MK,Rasoul BA,Segal RA,Pfister KK. A neuron-specific cytoplasmic dynein isoform preferentially transports TrkB signaling endosomes. J Cell Biol 2008; 181:1027-39. PubMed
  • Pazyra-Murphy MF,Segal RA. Preparation and maintenance of dorsal root ganglia neurons in compartmented cultures. J Vis Exp 2008. PubMed
  • 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; 55:53-68. PubMed
  • Redjal N, Chan JA, Segal RA, Kung AL. CXCR4 inhibition synergizes with cytotoxic chemotherapy in gliomas. Clin Cancer Res 2006; 12:6765-71. PubMed
  • Redjal N, Chan JA, Segal RA, Kung A. CXCR4 inhibtion syniergizes with cytotoxic chemotherapy in gliomas. J Am Diet Assoc 2006; In Press:In Press.
  • Choi Y, Borghesani PR, Chan JA, Segal RA. Migration from a mitogenic niche promotes cell-cycle exit. J Neurosci 2005; 25:10437-45. PubMed
  • Heerssen HM, Pazyra MF, Segal RA. Dynein motors transport activated Trks to promote survival of target-dependent neurons. Nat Neurosci 2004; 7:596-604. PubMed
  • Rubin JB, Kung AL, Klein RS, Chan JA, Sun 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; 100:13513-8. PubMed
  • Kim JY, Nelson AL, Algon SA, Graves O, Sturla LM, Goumnerova LC, Rowitch DH, Segal RA, Pomeroy SL. Medulloblastoma tumorigenesis diverges from cerebellar granule cell differentiation in patched heterozygous mice. Dev Biol 2003; 263:50-66. PubMed
  • Carter AR, Berry EM, Segal RA. Regional expression of p75NTR contributes to neurotrophin regulation of cerebellar patterning. Mol Cell Neurosci 2003; 22:1-13. PubMed
  • Wang KC, Kim JA, Sivasankaran R, Segal R, He Z. P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature 2002; 420:74-8. PubMed
  • Kim JY, Koralnik IJ, LeFave M, Segal RA, Pfister LA, Pomeroy SL. Medulloblastomas and primitive neuroectodermal tumors rarely contain polyomavirus DNA sequences. Neuro-oncol 2002; 4:165-70. PubMed
  • Bhattacharyya A, Watson FL, Pomeroy SL, Zhang YZ, Stiles CD, Segal RA. High-resolution imaging demonstrates dynein-based vesicular transport of activated Trk receptors. J Neurobiol 2002; 51:302-12. PubMed
  • Rubin JB, Choi Y, Segal RA. Cerebellar proteoglycans regulate sonic hedgehog responses during development. Development 2002; 129:2223-32. PubMed
  • Borghesani PR, Peyrin JM, Klein R, Rubin J, Carter AR, Schwartz PM, Luster A, Corfas G, Segal RA. BDNF stimulates migration of cerebellar granule cells. Development 2002; 129:1435-42. PubMed
  • Carter AR, Chen C, Schwartz PM, Segal RA. Brain-derived neurotrophic factor modulates cerebellar plasticity and synaptic ultrastructure. J Neurosci 2002; 22:1316-27. PubMed
  • Watson FL, Heerssen HM, Bhattacharyya A, Klesse L, Lin MZ, Segal RA. Neurotrophins use the Erk5 pathway to mediate a retrograde survival response. Nat Neurosci 2001; 4:981-8. PubMed
  • Klein RS, Rubin JB, Gibson HD, DeHaan EN, Alvarez-Hernandez X, Segal RA, Luster AD. SDF-1 alpha induces chemotaxis and enhances Sonic hedgehog-induced proliferation of cerebellar granule cells. Development 2001; 128:1971-81. PubMed
  • Choi DY, Toledo-Aral JJ, Segal R, Halegoua S. Sustained signaling by phospholipase C-gamma mediates nerve growth factor-triggered gene expression. Mol Cell Biol 2001; 21:2695-705. PubMed
  • O'Brien SP, Seipel K, Medley QG, Bronson R, Segal R, Streuli M. Skeletal muscle deformity and neuronal disorder in Trio exchange factor-deficient mouse embryos. Proc Natl Acad Sci U S A 2000; 97:12074-8. PubMed
  • Zhang Y, Moheban DB, Conway BR, Bhattacharyya A, Segal RA. Cell surface Trk receptors mediate NGF-induced survival while internalized receptors regulate NGF-induced differentiation. J Neurosci 2000; 20:5671-8. PubMed
  • Borghesani PR, Alt FW, Bottaro A, Davidson L, Aksoy S, Rathbun GA, Roberts TM, Swat W, Segal RA, Gu Y. Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice. Proc Natl Acad Sci U S A 2000; 97:3336-41. PubMed
  • Watson FL, Heerssen HM, Moheban DB, Lin MZ, Sauvageot CM, Bhattacharyya A, Pomeroy SL, Segal RA. Rapid nuclear responses to target-derived neurotrophins require retrograde transport of ligand-receptor complex. J Neurosci 1999; 19:7889-900. PubMed
  • Watson FL, Porcionatto MA, Bhattacharyya A, Stiles CD, Segal RA. TrkA glycosylation regulates receptor localization and activity. J Neurobiol 1999; 39:323-36. PubMed
  • Kim JY, Sutton ME, Lu DJ, Cho TA, Goumnerova LC, Goritchenko L, Kaufman JR, Lam KK, Billet AL, Tarbell NJ, Wu J, Allen JC, Stiles CD, Segal RA, Pomeroy SL. Activation of neurotrophin-3 receptor TrkC induces apoptosis in medulloblastomas. Cancer Res 1999; 59:711-9. PubMed
  • Ma Q, Jones D, Borghesani PR, Segal RA, Nagasawa T, Kishimoto T, Bronson RT, Springer TA. Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc Natl Acad Sci U S A 1998; 95:9448-53. PubMed
  • Schwartz PM, Levy RL, Borghesani PR, Segal RA. Cerebellar pathology in BDNF -/- mice: the classic view of neurotrophins is changing. Mol Psychiatry 1998; 3:116-20. PubMed
  • Pomeroy SL, Sutton ME, Goumnerova LC, Segal RA. Neurotrophins in cerebellar granule cell development and medulloblastoma. J Neurooncol 1998; 35:347-52. PubMed
  • Bhattacharyya A, Watson FL, Bradlee TA, Pomeroy SL, Stiles CD, Segal RA. Trk receptors function as rapid retrograde signal carriers in the adult nervous system. J Neurosci 1997; 17:7007-16. PubMed
  • Schwartz PM, Borghesani PR, Levy RL, Pomeroy SL, Segal RA. Abnormal cerebellar development and foliation in BDNF-/- mice reveals a role for neurotrophins in CNS patterning. Neuron 1997; 19:269-81. PubMed
  • Cabelli RJ, Shelton DL, Segal RA, Shatz CJ. Blockade of endogenous ligands of trkB inhibits formation of ocular dominance columns. Neuron 1997; 19:63-76. PubMed
  • Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM, Segal RA, Kaplan DR, Greenberg ME. Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 1997; 275:661-5. PubMed
  • Nachmanoff DB, Segal RA, Dawson DM, Brown RB, De Girolami U. Hereditary ataxia with sensory neuronopathy: Biemond's ataxia. Neurology 1997; 48:273-5. PubMed
  • Segal RA, Rua L, Schwartz P. Neurotrophins and programmed cell death during cerebellar development. Adv Neurol 1997; 72:79-86. PubMed
  • Segal RA, Bhattacharyya A, Rua LA, Alberta JA, Stephens RM, Kaplan DR, Stiles CD. Differential utilization of Trk autophosphorylation sites. J Biol Chem 1996; 271:20175-81. PubMed
  • Segal RA, Greenberg ME. Intracellular signaling pathways activated by neurotrophic factors. Annu Rev Neurosci 1996; 19:463-89. PubMed
  • Segal RA, Pomeroy SL, Stiles CD. Axonal growth and fasciculation linked to differential expression of BDNF and NT3 receptors in developing cerebellar granule cells. J Neurosci 1995; 15:4970-81. PubMed
  • Segal RA, Goumnerova LC, Kwon YK, Stiles CD, Pomeroy SL. Expression of the neurotrophin receptor TrkC is linked to a favorable outcome in medulloblastoma. Proc Natl Acad Sci U S A 1994; 91:12867-71. PubMed
  • Segal RA, Takahashi H, McKay RD. Changes in neurotrophin responsiveness during the development of cerebellar granule neurons. Neuron 1992; 9:1041-52. PubMed
  • Segal RA, Chapman C, Barlow J. Monozygotic twins with seizures. Shared characteristics. Arch Neurol 1991; 48:1041-5. PubMed
  • Segal RA, Luck DJ. Phosphorylation in isolated Chlamydomonas axonemes: a phosphoprotein may mediate the Ca2+-dependent photophobic response. J Cell Biol 1985; 101:1702-12. PubMed
  • Segal RA, Huang B, Ramanis Z, Luck DJ. Mutant strains of Chlamydomonas reinhardtii that move backwards only. J Cell Biol 1984; 98:2026-34. PubMed
  • Hsieh P, Segal R, Chen LB. Studies of fibronectin matrices in living cells with fluoresceinated gelatin. J Cell Biol 1980; 87:14-22. PubMed
  • Chen LB, Murray A, Segal RA, Bushnell A, Walsh ML. Studies on intercellular LETS glycoprotein matrices. Cell 1978; 14:377-91. PubMed
  • Krueger JG, Segal RA, Moyer RC. Differences in the responsiveness of splenic, lymph node, and peripheral blood lymphoid cells to tumor membrane extracts. Cancer Res 1976; 37:320-2. PubMed