Edward Giniger, Ph.D.
Axon Guidance and Neural Connectivity Section
Building 35, Room 1C1002
9000 Rockville Pike
Bethesda, MD 20892-4478
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.
Kuzina I, Song JK, Giniger E. How Notch establishes longitudinal axon connections between successive segments of the Drosophila CNS. Development. 2011;138(9):1839-49.
Trunova S, Baek B, Giniger E. Cdk5 regulates the size of an axon initial segment-like compartment in mushroom body neurons of the Drosophila central brain. J Neurosci. 2011;31(29):10451-62.
Spurrier J, Shukla AK, McLinden K, Johnson K, Giniger E. Altered expression of the Cdk5 activator-like protein, Cdk5α, causes neurodegeneration, in part by accelerating the rate of aging. Dis Model Mech. 2018;11(3).
Kannan R, Song JK, Karpova T, Clarke A, Shivalkar M, Wang B, Kotlyanskaya L, Kuzina I, Gu Q, Giniger E. The Abl pathway bifurcates to balance Enabled and Rac signaling in axon patterning in Drosophila. Development. 2017;144(3):487-498.
Kannan R, Cox E, Wang L, Kuzina I, Gu Q, Giniger E. Tyrosine phosphorylation and proteolytic cleavage of Notch are required for non-canonical Notch/Abl signaling in <i>Drosophila</i> axon guidance. Development. 2018;145(2).
Related Scientific Focus Areas
Genetics and Genomics
This page was last updated on August 3rd, 2018