Rosalind Segal 
 Address: Department of Pediatric Oncology
Dana-Farber Cancer Institute
44 Binney Street
Boston, MA 02115
Email: rosalind_segal@dfci.harvard.edu
 
Education:
1979 B.A. Harvard-Radcliffe University, summa cum laude (Biochemistry)

1985 Ph.D. Rockefeller University (Cell Biology)

1986 M.D. Cornell University

Postdoctoral Training:
1986-1987 Intern Medicine, Beth Israel Hospital, Boston, MA

1987-1990 Resident Neurology, Harvard Longwood Neurology Program Boston, MA

1990-1992 Postdoctoral Brain and Cognitive Sciences Fellowship Massachusetts Institute of Technology

1992-1994 Postdoctoral Cell and Molecular Biology, Dana-Farber Cancer Institute Fellowship Boston, MA

Licensure and Certification:
1990 Massachusetts Board of Registration in Medicine

1991 American Board of Psychiatry and Neurology

Academic Appointments:
1991-1994 Instructor in Neurology Harvard Medical School, Boston, Massachusetts

1994-1998 Assistant Professor in Harvard Medical School Neurology Boston, Massachusetts

1998-present Assistant Professor in Harvard Medical School Neurobiology Boston, Massachusetts

Hospital or Affiliated Institute Appointments:
1990-1993 Fellow in Neurology Children's Hospital Boston, Massachusetts

1993-1995 Associate in Neurology Beth Israel Deaconess Medical Center Boston, Massachusetts

1995-1998 Senior Associate in Beth Israel Deaconess Medical Center Neurology Boston, Massachusetts

1998-present Department of Pediatric Dana-Farber Cancer Institute Oncology Boston, Massachusetts

Hospital and Health Care Organization Service Responsibilities:
1995-1997 co-Director, Brain Tumor Group Beth Israel Deaconess Medical Center Boston, Massachusetts

1998- Neurology Consultant Perini Clinic, Dana-Farber Cancer Institute

Major Committee Assignments:
1984-1985 Rockefeller University Lecture Committee

1993-1996 Beth Israel Cancer Committee

1997-1998 Beth Israel-Deaconess Grants Review

1997-2000 M.D.-Ph.D. Admissions Committee

1998-2000 Neuroscience Program Admissions Committee

1998-2000 Neuroscience Program Steering Committee

1998-2001 Neuronal Ceroid Lipofuscinosis Alliance Advisory Board

2000- MD/PhD Clinical Curriculum Committee

2000- Barr Grant Review Committee Program

Professional Societies:
Society for Neuroscience American Academy of Neurology

Editorial Boards:
1995-1999 ad hoc reviewer for: Neuron, J. Neuroscience, J.Comp. Neurol., Mol.Cell. Bio., J. Neurobiol., Endocrinology, Genes and Development, Nature Genetics

1999 ad hoc reviewer N.I.H. study section MDCN6, ad hoc reviewer Christopher Reeves Foundation, National Science Foundation

Awards and Honors:
1975-1976 National Merit Scholarship
1979 Phi Beta Kappa
1979-1980 National Science Foundation Pre-doctoral Fellowship
1980-1986 Medical Science Training Program Pre-doctoral Fellowship
1990-1991 Dana Foundation Postdoctoral Fellowship
1996-1999 Robert Ebert Clinical Scholar Klingenstein Award
1998-2000 Claudia Adams Barr Investigator
2001-2003 McDonnell Foundation Award

Part II: Research, Teaching, and Clinical Contributions
A. Our lab is interested in the mechanisms by which extracellular stimuli regulate development and functioning of the nervous system. The neurotrophin brain-derived neurotrophic factor (BDNF) promotes survival and axonal elongation of developing granule cells. In contrast, the highly related factor neurotrophin-3 (NT-3) has distinct effects on development, regulating the acquisition of a mature phenotype . To examine the roles of these factors in vivo, we have made use of mice with mutations in the genes encoding neurotrophins or their receptors. Mice with a targeted gene deletion of brain-derived neurotrophic factor (BDNF) exhibit an ataxic gait. Consistent with this behavioral evidence of cerebellar dysfunction, there is increased death of developing granule cells, stunted growth of Purkinje cell dendrites, impaired formation of horizontal layers, and defects in the rostral-caudal foliation pattern. These abnormalities are accompanied by decreased Trk activation in granule and Purkinje cells of mutant animals, indicating that both cell types are direct targets for BDNF. These data suggest that BDNF acts as an anterograde and an autocrine/paracrine factor to regulate survival and morphologic differentiation of developing CNS neurons, and thereby affects neural patterning. Understanding the mechanisms of action of neurotrophins in normal neurons requires a consideration of spatial constraints. For a target derived neurotrophin to regulate the survival of a presynaptic cell, a signal must be propagated from the nerve terminal along the axon to the nucleus. The adaptations required for this retrograde signaling are, as yet, unknown. We are using the sciatic nerve of adult rat, and compartmented chamber cultures of embryonic neurons as systems in which to identify the molecule(s) that carry the signal(s) along the axon, and the mechanism for signal propagation. Using phosphorylation state specific antibodies to neurotrophin receptors (Trks) we demonstrated that phosphorylated Trks distributed all along the length of sciatic nerve axons are catalytically active and are associated with signal generating proteins. Neurotrophins applied at the nerve terminal activate distant axonal Trk receptors, and this activation propagates rapidly through the axon toward the nerve cell body. Thus, activated Trk receptors function as rapid retrograde signal carriers to elicit nuclear responses to target derived neurotrophins. Once they reach the cell body, activated receptors elicit nuclear responses- including phosphorylation of the transcription factor CREB and subsequent induction of the immediate early gene c-fos. We used GFP-tagged Trk receptors to determine the mechanism by which the retrograde phospho-Trk signal is propagated. Our data indicate that signal propagation represents retrograde vesicular transport of activated Trk-ligand complexes.. We have found that the transported receptors use novel MAP kinase pathways to communicate with the nucleus, and to induce transcriptional changes to growth factors. These data support a model of retrograde signaling whereby rapid vesicular transport of ligand-receptor complex from the neurites to the cell bodies uses distinct MAP kinase pathways to mediate nuclear responses.

B. Funding Information
09/01/79 - 06/30/80 National Science Foundation Predoctoral Fellowship

07/01/80 - 06/30/86 NIH Medical Scholar Training Program

07/01/90 - 06/30/91 Dana Foundation Neuroscience Fellowship

07/01/91 - 06/30/96 NIH Clinical Investigator Development Award

01/01/95 - 12/30/95 National Ataxia Foundation Apoptosis in Cerebellar Development

05/01/96 - 04/31/03 NIH Retrograde Signal Transduction by Neurotrophins

07/01/96 - 06/30/99 Klingenstein Mechanisms of retrograde signaling Foundation

07/01/96 - 06/30/97 Hearst Foundation Neurotrophins in Cerebellar Development

06/01/97 - 06/01/98 Ataxia Telangiectasia Mouse Model for A.T. Children's Project

07/01/98 - 06/30/02 NIH Cell-cell interactions in Cerebellar Development

01/01/01-12/30/03 McDonnell Foundation Genetic Modifiers of Medulloblastoma

C. Current Research Activities:
Project: Cell:Cell interactions in cerebellar development P.I. Retrograde signaling by neurotrophins P.I. Genetic modifiers of medulloblastoma P.I.

D.Teaching Experience:
1992, 1994 Cell and Developmental Biology, CDB 212B, The animal cell growth factors, Harvard Medical School Role lecturer 15 students (graduate students) Contact time- 4-6 hours Preparation time- 10-20 hours

1997 Neurobiology 207-Developmental Neurobiology Harvard Medical School Role lecturer 20 students (graduate students) contact time: 40 hours preparation time: 30-40 hours 1998 Introductory Neuroscience Harvard Medical School Role lecturer 100 students (medical students) contact time : 2 hours preparation time 5 hours

1999, 2001 Neurobiology 207-Developmental Neurobiology, Harvard Medical School Role Course organizer 20 students (graduate students) contact time: 50 hours preparation time : 50 hours

F. Trainees:

Period of Training Name Lab Position Current Position
09/96-01/97 Lisa Catapano Rotation Project Predoctoral Fellow Harvard Medical School
01/98-04/98 Jane Ko Rotation Project Predoctoral Fellow Harvard Medical School
07/98-10/98 Carolyn Rodriquez Rotation Project  Predoctoral Fellow Harvard Medical School
11/99- 2/00 Yoojin Choi  Rotation Project Predoctoral Fellow Harvard Medical School

H. Predoctoral and Postdoctoral Students

Period of Training Name Lab Position Current Position
1994-1998  Phillip Schwartz  Predoctoral, Ph.D. 1998  Consultant, Cap Gemini Ernst & Young LLP 
1996-1997 Rich Levy Predoctoral, Intern in Medicine M.D. 1997 Lenox-Hill Hospital,NY
1995-present  Fiona Watson  Predoctoral, Ph.D. 1999  Postdoctoral Fellow, Dana-Farber Cancer Institute
1996-present  Paul Borghesani Predoctoral M.D.-Ph.D. expected Harvard June 2001  
1998-present Alex Carter Predoctoral Ph.D. Thesis work  
1998-present Heather Heersen Predoctoral Ph.D. Thesis work  
2000-present Yoojin Choi Predoctoral Ph.D. Thesis work  
1996-present  Yanzhen Zhang Postdoctoral Fellow Dana-Farber Cancer Institute
1998-present  Joshua Rubin  Postdoctoral Fellow Dana-Farber Cancer Institute
1999-2000  Yvonne Yannoni  Postdoctoral Fellow Genetics Institute
 

2. Regional, national, or international contributions:
Invited Lectures: Asilomar Converence: Neuronal Plasticity and repair 1996.
University of Cincinnati 1997
American Academy of Neurology Faculty (1997,1998,1999)
Gordon Conference "Neurotrophic Factors1997
Case Western Reserve University 1998
Uniform Health Services University
1998 Brandeis University
1999 Children's Hospital
1999 American Society for Neurochemistry
2000 Johns Hopkins University
1999 University of Massachusetts Medical Center
2000 Mount Sinai Medical Center
2000 Gordon Conference "Cell Biology of the Neuron"
2000 Wood's Hole Marine Biology Laboratory, Course in Neurobiology
2000 Columbia University Medical School 2001

Patent Information:
Patent application number: PCT/US99/02871 NT3 in Medulloblastoma

PART III: Bibliography
Original Reports:
1. Krueger J, Segal RA, Moyers R. 1977. Differences in the responsiveness of splenic, lymph node and peripheral blood lymphoid cells to tumor membrane extracts. Cancer Res. 37: 320-322.

2.Chen LB, Murray A, Segal RA, Buchnell A, Walsh ML. 1978. Studies on intracellular LETS glycoprotein matrices. Cell 14: 377-391.

3. Hsieh P, Segal RA, Chen LB. 1980. Studies of fibronectin matrices in living cells with fluoroscinated gelatin. J. Cell Biol. 87: 14-22.

4. Segal RA, Huang B, Ramanis Z, Luck DJL. 1984. Mutant strains of Chlamydomonas reinhardtii that move backwards only. J. Cell Biol. 1984; 98: 2026-2034.

5. Segal RA, Luck DJL. 1985. Phosphorylation in isolated Chlamydomonas axonemes: A phosphoprotein may mediate the Ca+2-dependent photophobic response. J. Cell Biol. 101: 1702-1712.

6. Segal RA, Chapman C, Barlow J. 1991. Monozygotic twins with seizures: shared characteristics. Arch. Neurol. 48: 1041-1048.

7. Segal RA, Takahashi H, McKay R. 1992. Changes in neurotrophin responsiveness during the development of cerebellar granule neurons. Neuron 1992; 9: 1041-1052.

8. Segal RA, Goumnerova LC, Kwon YK, CD Stiles CD, Pomeroy SL. 1994. Expression of the neurotrophin receptor trkC is linked to a favorable outcome in medulloblastoma. Proc. Nat. Acad. Sci. USA. 1994; 91: 12867-12871.

9. Segal RA, Pomeroy SL, Stiles CD. 1995. Axonal growth and fasciculation linked to differential expression of BDNF and NT3 receptors in developing cerebellar granule cells. J. Neurosci. 15: 4970-4981.

10. Segal RA, Bhattacharyya A, Rua L, Alberta JA, Stephens RM, Kaplan DR, Stiles CD. 1996. Differential utilization of Trk autophosphorylation sites in vivo. J. Biol. Chem. 271:20175-20181.

11. Nachmanoff D, Segal RA, Brown RB, De Girolami U, Dawson DM. Hereditary ataxia with sensory neuronopathy: Biemond's ataxia. Neurology, 1997; 48:273-275.

12. Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM, Segal RA, Kaplan DR, Greenberg ME. 1997. Regulation of neuronal survival by the ser/thr protein kinase Akt. Science, 1997; 275: 661-665.

13. Cabelli RJ, Shelton D, Segal RA, Shatz CJ. 1997. An endogenous ligand of TrkB is required for ocular dominance segregation. Neuron 19: 63-76.

14. Schwartz PM, Borghesani, Levy RL, Pomeroy SL, Segal RA. 1997. Abnormal cerebellar development and foliation in BDNF -/- mice reveals a role for neurotrophins in CNS patterning. Neuron 19: 269-281

15. Bhattacharyya A, Watson FL, Bradlee TA, Pomeroy SL, Stiles CD, Segal RA. 1997. Trk receptors function as retrograde signal carriers in the adult nervous system. J. Neurosci., 17:7007-7016.

16. Schwartz PM, Borghesani PR, Levy RL, Segal RA. 1998. Cerebellar pathology in BDNF -/- mice: The classic view of neurotrophins is changing. Molecular Psychiatry, 3: 116-118.

17. Ma Q, Jones D, Borghesani PR, Segal RA, Nagasawa T, Kishimoto T, Bronson, RT, Springer TA. 1998. Impaired B-Lymphopoiesis, myelopoiesis and derailed cerebellar neuron migration in CXCR4 and SDF-1 deficient mice. Proc. Nat.Acad. Sci. USA. 95: 9448-53.

18. Kim J, Sutton ME, Lu DJ, Cho TA, Goumnerova LC, Goritchenko L, Lam KK, Allen JC, Wu J, Tarbell NJ, Billett AL, Segal RA, Pomeroy SL. 1999. High NT-3 receptor expression and apoptosis in favorable medulloblastomas. Cancer Research 59: 711-719.

19. Watson FL, Porcionatto MA, Bhattacharyya A, Stiles CD, Segal RA. 1999. TrkA Glycosylation regulates receptor localization and activity. J. Neurobiology, 39:323-336.

20. Watson FL, Heersson HM, Moheban DB, Lin MZ, Sauvageot CM, Pomeroy SL, Bhattacharyya A, Segal RA. 1999. Rapid nuclear responses to target derived neurotrophins require retrograde transport of ligand-receptor complex. J. Neurosci. 19:7889-7900.

21. Borghesani PR , Alt FW, Bottaro A, Davidson L, Aksoy S, Rathbun GA, Roberts TM, Swat W, Segal RA, Gu Y. 2000. Abnormal Development of Purkinje Cells and Lymphocytes in Atm Mutant Mice. Proc. Nat. Acad. Sci. USA, 97(7):3336-41.

22. Zhang YZ, Moheban DB,. Conway BR, Bhattacharyya A, Segal RA. 2000. Cell surface Trk receptors mediate NGF-induced survival while internalized receptors regulate NGF-induced differentiation. J. Neurosci, 20, 5671-5678.

23. O'Brien SP, Seipel K, Medley QG, Bronson R, Segal R, Streuli M. 2000. Skeletal muscle deformity and neuronal disorder in Trio exchange factor-deficient mouse embryos. Proc Natl Acad Sci U S A ;97(22):12074-12078.

24. Deog-Young Choi, Juan J Toledo-Aral, Rosalind A. Segal, Simon Halegoua. Sustained signaling by PLCg mediates NGF-triggered gene expression. Mol. Cell Biol., in press.

25. Robyn S. Klein, Joshua B. Rubin=, Hilary D. Gibson, Elliot N. DeHaan, Xavier Alvarez-Hernandez, Rosalind A. Segal, and Andrew D. Luster. SDF-1a induces chemotaxis and enhances Sonic hedgehog-induced proliferation of cerebellar granule cells. Development, in press.

26. Paul R. Borghesani, Jean Michel Peyrin, Joshua Rubin, Alexandre R. Carter, Phillip M. Schwartz, Li-Hue Tsai, Gabriel Corfas, Rosalind A. Segal. Neuronal migration promotes cell cycle exit. Neuron, revised manuscript submitted.

Reviews and Book Chapters:
1. Segal RA and Greenberg ME. 1996. Intracellular signaling pathways activated by neurotrophic factors. Annu. Rev. Neurosci. 19: 463-489

2. Segal RA, Rua L , Schwartz P. 1997. Neurotrophins and programmed cell death during cerebellar development. Advances in Neurology vol 72, Chapter 8.

3. Pomeroy SL and Segal RA. "Development of the Nervous System" in Neonatal and Fetal Medicine , Poland RA and Fox WW eds. Philadelphia, Saunders.

4. Pomeroy SL, Sutton ME, Goumenrova LC, Segal RA. 1997. Neurotrophins in cerebellar granule cell development and medulloblastoma. J.Neuro-Oncology , 35: 347-352.

6. Alberta JA and Segal RA. Current Protocols in Neuroscience Unit 3.6 Generation and utilization of phosphorylation-state specific antibodies to investigate neuronal signaling pathways.

7. Alexandre R. Carter and Rosalind A. Segal. Rett syndrome suggests methyl-CpG binding protein 2 provides neurons with the quiet they need to think. Nature Neuroscience, in press.

Abstracts:
SL Pomeroy, LC Goumnerova, YK Kwon, CD Stiles, RA Segal. Coordinate expression of neurotrophin-3 and TrkC linked to a more favorable prognosis in medulloblastoma. 1994. Soc. Neurosci. Abstr. Vol 20, Part 2, p. 1105.

A Bhattacharyya, L Rua, DR Kaplan, CD Stiles, RA Segal. Generation of antibodies to activated Trk receptors. 1994 Soc. Neurosci. Abstr. Vol 20, Part 1, p. 38.

PM Schwartz, PR Borghesani, RL Levy, RA Segal. 1997. Abnormal cerebellar development and foliation in BDNF -/- mice reveals a role for neurotrophins in CNS patterning. Soc. Neurosci. Abstr. Vol 23, part 1, p. 59.

A Bhattacharyya, FL Watson, TA Bradlee, SL Pomeroy, CD Stiles, RA Segal. 1997. Trk receptors function as rapid retrograde signal carriers in the adult nervous system. Soc. Neurosci. Abstr. Vol 23, part 2, p.1433.