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Senior Investigator

Edward Giniger, Ph.D.

Axon Guidance and Neural Connectivity Section


Building 35 Room 1C1002
9000 Rockville Pike MSC 3702
Bethesda MD 20892-4478
Office: (301) 451-3890
Lab: (301) 451-3890
Fax: (301) 480-5368
ginigere@ninds.nih.gov

Dr Giniger received his BS from Yale University (1979) and his PhD from Harvard (1988), the latter studying the yeast regulatory protein, GAL4, with Dr Mark Ptashne. Dr Giniger then turned to postdoctoral work with Dr Yuh Nung Jan at UCSF. There, he initiated a two-pronged series of studies of axon guidance in Drosophila, investigating the mechanism by which a particular cell surface receptor (Notch) guides developing axons, and also how one transcription factor (Lola) coordinates the effects of many guidance receptors to ensure the accuracy of neural wiring. Dr Giniger continued this work while on the faculty of the Fred Hutchinson Cancer Research Center, in Seattle, WA, prior to joining NINDS as an Investigator in 2004. Dr Giniger continues to study both the mechanism and the basis of fidelity in axon guidance, while also expanding his focus to investigate the role of developmental genes in adult-onset neurodegenerative diseases.



How do neurons become connected during development? Why do they become disconnected during neurodegenerative disease?

Axon guidance For a receptor at the cell surface to make an axon grow, its activity has to be channeled by intracellular signaling cascades to control cytoskeletal dynamics. This is the most fundamental process in axon guidance, but how does it happen? To find out, we study modulation of the Abl tyrosine kinase signaling network by the receptor Notch in the Drosophila nervous system. Using molecular and classical genetics, biochemistry, and live imaging of growing axons with fluorescent bioprobes, we are seeing how the intrinsic structure of the Abl network decomposes the single input from the receptor into a linked constellation of outputs that coordinately regulate the dynamics of different actin-rich structures of the growth cone (filopodia and lamellipodia), and coordinate both with substratum adhesion, to yield directed axon growth in vivo.

Neurodegeneration The greatest gap in our understanding of neurodegenerative disease is right at the initiation of the process: what are the first things that go wrong in cells as they begin the progression to degeneration? We can now initiate at will a natural, adult-onset neurodegenerative syndrome in Drosophila by inactivation of Cdk5, the fly ortholog of a gene associated with many forms of neurodegeneration in humans, including Alzheimers, ALS and Parkinsons. By moving back in time to the earliest stages of disease onset in our mutant, we have found two completely unexpected effects of Cdk5 that are likely to be directly related to disease initiation. First, Cdk5 is required to build the axon initial segment of the cell, where action potentials initiate, suggesting that deregulation of Cdk5 during disease will grossly disrupt neuronal activity far in advance of overt degeneration. Second, Cdk5 controls disassembly of axons and dendrites during programmed, developmental remodeling of neurons, and it is likely that this same activity is responsible for pathological disassembly of neurons during disease.

Staff Image
  • 1) Kuzina, I., Song, J.K. and Giniger, E. (2011)
  • How Notch establishes longitudinal axon connections between successive segments of the Drosophila CNS
  • Development , 138, 1839-49
  • 2) Trunova, S., Baek, B. and Giniger, E. (2011)
  • Cdk5 regulates the size of an AIS-like compartment in mushroom body neurons of the Drosophila central brain
  • J. Neurosci, 31, 10451-62
  • 3) Song, J.K., Kannan, R., Merdes, G., Singh, J., Mlodzik, M. and Giniger, E. (2010)
  • Disabled is a bona fide component of the Abl signaling network
  • Development, 137, 3719-3727
  • 4) Le Gall, M., DeMattei, C. and Giniger, E. (2008)
  • Molecular separation of two signaling pathways for the receptor, Notch
  • Dev. Biol, 313, 556-567
  • 5) Crowner, D., Le Gall, M., Gates, M.A., and Giniger, E. (2003)
  • Notch steers Drosophila ISNb motor axons by regulating the Abl signaling pathway
  • Curr Biol , 13, 967-972
  • 6) Goeke, S., Greene, E.A., Gates, M.A., Grant, P.K., Crowner, D., Aigaki, T. and Giniger, E. (2003)
  • Alternative splicing of lola generates 19 transcription factors controlling axon guidance in Drosophila
  • Nature Neuroscience , 6, 917-924
  • 7) Giniger, E. (2002)
  • How do Rho family GTPases direct axon growth and guidance? A proposal relating signaling pathways to growth cone mechanics
  • Differentiation , 70, 385-396
  • 8) Connell-Crowley, L., Le Gall, M., Vo, D. and Giniger, E. (2000)
  • Cdk5 controls multiple aspects of axon patterning in vivo.
  • Curr Biol , 10, 599-602
  • 9) Bothwell, M. and Giniger, E. (2000)
  • Alzheimer's Disease: Neurodevelopment Converges with Neurodegeneration
  • Cell , 102, 271-273
  • 10) Hiramoto, M., Hiromi, Y., Giniger, E. and Hotta, Y. (2000)
  • A Drosophila Netrin receptor, Frazzled, guides axons by controlling the distribution of Netrin
  • Nature , 406, 886-889
  • 11) Ostrander, E. A. and Giniger, E. (1999)
  • Let sleeping dogs lie?
  • Nature Genetics , 23, 3-4
  • 12) Madden, K., Crowner, D. and Giniger, E. (1999)
  • lola has the properties of a master regulator of axon-target interactions for SNb motor axons of Drosophila
  • Dev. Biol, 301-313, 213
  • 13) Fuerstenberg, S. M. and Giniger, E. (1998)
  • Multiple roles for Notch in Drosophila myogenesis
  • Dev. Biol, 201, 66-77
  • 14) Ostrander, E. A. and Giniger, E. (1997)
  • What man's best friend can teach us about human biology and disease
  • Am. J. Hum. Genet, 61, 475-80
  • 15) Larkin, M. K., Holder, K., Yost, C., Giniger, E. and Ruohola-Baker, H. (1996)
  • Expression of constitutively active Notch arrests follicle cells at a precursor stage during Drosophila oogenesis and disrupts the anterior-posterior axis of the oocyte
  • Development , 3639-3650, 122
  • 16) Giniger, E., Tietje, K., Jan, L. Y. and Jan, Y. N. (1994)
  • lola encodes a putative transcription factor required for axon growth and guidance in Drosophila
  • Development , 120, 1385-98
  • 17) Clark, I., Giniger, E., Ruohola-Baker, H., Jan, L. Y. and Jan, Y. N. (1994)
  • Transient posterior localization of a kinesin fusion protein reflects anteroposterior polarity of the Drosophila oocyte
  • Curr. Biol, 4, 289-300
  • 18) Giniger, E., Wells, W., Jan, L. Y. and Jan, Y. N. (1993)
  • Tracing neurons with a kinesin-ƒÒ-galactosidase fusion protein.
  • Roux's Arch Dev Biol , 202, 112-122
  • 19) Giniger, E., Jan, L. Y. and Jan, Y. N. (1993)
  • Specifying the path of the intersegmental nerve of the Drosophila embryo: a role for Delta and Notch
  • Development , 117, 431-440
  • 20) Giniger, E. and Ptashne, M. (1988)
  • Cooperative binding of the yeast transcriptional activator, GAL4
  • Proc Natl Acad Sci, USA , 85, 382-386
  • 21) Giniger, E. (1988)
  • A role for abl in Notch signaling
  • Neuron , 20, 667-681
  • 22) Fischer, J. A., Giniger, E., Maniatis, T. and Ptashne, M. (1988)
  • GAL4 activates transcription in Drosophila.
  • Nature , 332, 853-856
  • 23) Giniger, E. and Ptashne, M. (1987)
  • Transcription in yeast activated by a putative amphipathic ƒÑ-helix linked to a DNA-binding unit
  • Nature , 330, 670-672
  • 24) Giniger, E., Varnum, S. M. and Ptashne, M. (1985)
  • Specific DNA binding of GAL4, a positive regulatory protein of yeast.
  • Cell , 40, 767-774
  • 25) Wagner, P. D. and Giniger, E. (1981)
  • Hydrolysis of ATP and reversible binding to F-actin by myosin heavy chains free of all light chains
  • Nature , 292, 560-562
  • 26) Wagner, P. D. and Giniger, E. (1981)
  • Calcium-sensitive binding of heavy meromyosin to regulated actin in the presence of ATP
  • J Biol Chem , 256, 12647-12650
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