Axon Guidance and Neural Connectivity Unit - Division of Intramural Research

Edward  Giniger, Ph.D., Investigator

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.

Research Interests

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.

Selected Recent Publications

Kuzina, I., Song, J.K. and Giniger, E.
How Notch establishes longitudinal axon connections between successive segments of the Drosophila CNS - Development   138 1839-49 2011, 

Trunova, S., Baek, B. and Giniger, E.
Cdk5 regulates the size of an AIS-like compartment in mushroom body neurons of the Drosophila central brain - J. Neurosci  31 10451-62 2011, 

Song, J.K., Kannan, R., Merdes, G., Singh, J., Mlodzik, M. and Giniger, E.
Disabled is a bona fide component of the Abl signaling network - Development  137 3719-3727 2010, 

Le Gall, M., DeMattei, C. and Giniger, E.
Molecular separation of two signaling pathways for the receptor, Notch - Dev. Biol  313 556-567 2008, 

Goeke, S., Greene, E.A., Gates, M.A., Grant, P.K., Crowner, D., Aigaki, T. and Giniger, E.
Alternative splicing of lola generates 19 transcription factors controlling axon guidance in Drosophila - Nature Neuroscience   6 917-924 2003, 

Crowner, D., Le Gall, M., Gates, M.A., and Giniger, E.
Notch steers Drosophila ISNb motor axons by regulating the Abl signaling pathway - Curr Biol   13 967-972 2003, 

Giniger, E.
How do Rho family GTPases direct axon growth and guidance? A proposal relating signaling pathways to growth cone mechanics - Differentiation   70 385-396 2002, 

Selected Earlier Publications

Contact Information

Axon Guidance and Neural Connectivity Unit, NINDS Building 35, Room 1C1002, MSC 3702  9000 Rockville Pike   Bethesda MD  20892-4478

Telephone: 301-451- 3890 (office), 301- 451-3890 (laboratory), 301-480- 5368 (fax), Email: ginigere@ninds.nih.gov