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Axon Guidance and Neural Connectivity Unit
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:
To understand how the nervous system gets wired-up during development, we need to ask a few, related questions: 1. What is the mechanism by which a single guidance receptor directs the growth of an axon? 2. How are the signals from many receptors integrated in the growth cone? 3. Why doesn't this complex machine make mistakes?
We use classical and molecular genetics, in vitro biochemistry, genomic approaches and in vivo imaging to attack these questions in the Drosophila nervous system.
1. Mechanism of a guidance choice: A non-canonical Notch signaling pathway controls actin dynamics. Notch is a highly conserved cell surface receptor that determines cell fates throughout the embryo. We have found that Notch has a second career as a growth cone guidance receptor. In this connection, Notch cooperates with the Abl tyrosine kinase, associating with Abl accessory factors to control the Rac GTPase and, ultimately, local actin dynamics. Current directions include genetic and mass spectrometric identification of components of the non-canonical "Notch/Abl" signaling pathway, determination of the mechanism of Notch/Abl signaling, and in vivo imaging of signaling in live neurons to see exactly how Notch activity produces specific guidance choices.
2. Basis of fidelity in neural wiring. Neural connectivity is incredibly complex, so why don't axons make guidance mistakes? Our data suggests that a cyclin-dependent kinase, Cdk5, acts in growth cones to ensure the accuracy of neural wiring. We hypothesize that Cdk5 defines a homeostatic feedback loop that stabilizes signaling from a receptor (Notch) to the cytoskeleton (via Abl and Rac), thereby preventing stochastic fluctuations that cause guidance errors. Current directions center on establishing the mechanism and significance of the feedback loop. We have recently also found that a fly mutant lacking Cdk5 activity displays an adult-onset neuropathy, characterized by progressive loss of motor coordination, rigidity and premature death. This potentially provides a way to use simple loss of function mutations in flies to study neurodegenerative diseases, including Alzheimer disease.
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Selected Publications:
- Le Gall, M. and Giniger, E. (2004) Identification of two binding regions for the Suppressor of Hairless protein within the intracellular domain of Drosophila Notch, J. Biol. Chem 279, 29418-29426.
- Horiuchi, T. Giniger, E. and Aigaki, T. (2003) Alternative trans-splicing of constant and variable exons of a Drosophila axon guidance gene, lola, Genes Dev 17, 2496-2501.
- 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.
- 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.
- Crowner, D., Madden, K., Goeke, S. and Giniger, E. (2002) Lola regulates midline crossing of CNS axons in Drosophila, Development 129, 1317-1325.
- 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.
All Selected Publications
Contact Information:
Dr. Edward Giniger
Axon guidance and neural connectivity Unit, NINDS
Building 37, Room 1016A, MSC 4478
9000 Rockville Pike
Bethesda, MD 20892-4478
Telephone: 301-451-3890 office,
301-451-3890 laboratory,
301-480-1485 fax
Email: ginigere@ninds.nih.gov
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