Axon Guidance and Neural Connectivity Unit - Division of Intramural Research

Edward Giniger, Ph.D., Investigator

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, 2011, vol. 138, pp. 1839-49.
• 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, 2011, vol. 31, pp. 10451-62.
• 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, 2010, vol. 137, pp. 3719-3727.
• Le Gall, M., DeMattei, C. and Giniger, E.
  Molecular separation of two signaling pathways for the receptor, Notch, Dev. Biol, 2008, vol. 313, pp. 556-567.
• 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, 2003, vol. 6, pp. 917-924.
• 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, 2003, vol. 13, pp. 967-972.
• Giniger, E.
  How do Rho family GTPases direct axon growth and guidance? A proposal relating signaling pathways to growth cone mechanics, Differentiation, 2002, vol. 70, pp. 385-396.
• Hiramoto, M., Hiromi, Y., Giniger, E. and Hotta, Y.
  A Drosophila Netrin receptor, Frazzled, guides axons by controlling the distribution of Netrin, Nature, 2000, vol. 406, pp. 886-889.

Selected Earlier Publications

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