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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) 594-9668
Fax: (301) 480-5368
ginigere@ninds.nih.gov

Dr Giniger received his BS from Yale University (1979) and his Ph.D. from Harvard (1988), the latter studying the yeast transcriptional activator, GAL4, with Dr Mark Ptashne. Dr Giniger then turned to postdoctoral work with Dr Yuh Nung Jan at UCSF, where he initiated studies of axon guidance in Drosophila. 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 the mechanism of axon guidance, using in vivo live imaging, biochemistry and genetics to investigate how cytoplasmic signaling pathways interpret external guidance cues to direct axon growth. In recent years, his lab has also begun to investigate adult-onset neurodegenerative diseases. In particular, he seeks to understand how aging interacts with defects in the homeostatic machineries of the neuron, and of the organism, to cause progressive disruption of neural circuits and neuron loss.

 



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, and grow in the right direction, 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 Drosophila. Using molecular and classical genetics, biochemistry, and in vivo live imaging of growing axons with fluorescent bioprobes, we have been led to an entirely novel and unexpected model for how Abl signaling directs axon growth. We find that Abl simply introduces a subtle spatial bias into the intrinsic, stochastic fluctuations of the axon cytoskeleton, thus gently nudging the growing axon along just the right trajectory by modulating the inherent dynamics of actin networks. Ongoing efforts focus on visualizing the molecular interactions that execute this mechanism, and on computational modeling to both challenge and refine our new picture of axon growth.

 

Neurodegeneration:  Research in many labs has revealed a host of physiological processes whose dysfunction contribute to neurodegenerative disease: proteostasis, mitochondrial function, innate immunity, neuronal excitability, axonal integrity, and above all, aging. But what are the connections between these processes? How does their interaction produce the overall outcome of nervous system degeneration? By studying a simple, endogenous neurodegenerative syndrome in Drosophila – gain- or loss-of function of the Cdk5/p35 protein kinase - we can now show that these degenerative processes separate into three, largely parallel mechanisms that interact synergistically to cause death of neurons. First, altering Cdk5 activity disrupts the integrity of the axonal cytoskeleton, leading to axon swelling and fragmentation, and also to loss of the specialized axonal domain where action potentials initiate. Second, altering Cdk5 inhibits autophagy, which in turn hyperactivate the innate immune system, causing release of neurotoxic quantities of anti-microbial peptides. Third, altering Cdk5 accelerates the absolute rate of aging, thus producing an overall organismal fragility, exacerbating the consequences of the other two degenerative pathways and, together, leading to disconnection and death of the neuron. Ongoing efforts focus on identifying the direct links between Cdk5 and each of these pro-degeneration pathways, and in particular on identifying how their effects can be reduced or eliminated to restore neuron health.

 

Staff Image
  • Aravind Chandrasekaran, RN, BSN, CCRP
    Predoctoral Fellow

  • Akanni Clarke, Ph.D.
    Postdoctoral Researcher

  • Christina Fang, Ph.D.
    Postdoctoral Researcher

  • Joy Gu, Ph.D.
    Technician

  • Irina Kuzina, Ph.D.
    Technician

  • Kate O'Neill, Ph.D.
    Postdoctoral Researcher

  • Arvind Shukla, Ph.D.
    Postdoctoral Researcher

  • 1) Shukla, A.K., Spurrier, J., Kuzina, I. and Giniger, E (2019)
  • Hyperactive innate immunity causes degeneration of dopamine neurons upon altering activity of Cdk5
  • Cell Reports, 26(1):131-144.e4, doi: 10.1016/j.celrep.2018.12.025
  • 2) Hunter, G.L., He, L., Perrimon, N., Charras. G., Giniger, E. and Baum, B (2019)
  • Notch-mediated tissue patterning requires actomyosin contractility
  • BMC Biology, 17(1):12, doi: 10.1186/s12915-019-0625-9
  • 3) Clarke, A., McQueen, P., Fang, H.-Y., Kannan, R., Wang, V., McReedy, E., Wincovitch, S. and Giniger, E (2019)
  • Abl signaling shapes the intrinsic fluctuations of actin to direct growth of a pioneer axon in Drosophila
  • bioRciv, doi: https://doi.org/10.1101/511840
  • 4) Spurrier J, Shukla AK, Buckley T, Smith-Trunova S, Kuzina I, Gu Q, Giniger E (2019)
  • Expression of a fragment of Ankyrin 2 disrupts the structure of the axon initial segment and causes axonal degeneration in Drosophila
  • NULLMol Neurobiol , 21-Jan . doi: 10.1007/s12035-019-1477-6, [Epub ahead of print]
  • 5) Kannan, R., Cox, E., Wang, L., Kuzina, I., Gu, Q. and Giniger, E (2018)
  • Tyrosine phosphorylation and proteolytic cleavage of Notch are required for non-canonical Notch/Abl signaling in Drosophila axon guidance
  • Development, 145, pii: dev151548
  • 6) Spurrier, J., Shukla, A.K., McLinden, K., Johnson, K. and Giniger, E (2018)
  • Altered expression of the Cdk5 activator-like protein, Cdk5a, causes neurodegeneration in part by accelerating the rate of aging
  • Dis Models Mech, 11, dmm031161.
  • 7) Kannan, R., J.K. Song, T. Karpova, A. Clarke, M. Shivalkar, B. Wang, L. Kotlyanskaya, I. Kuzina, Q. Gu, and Giniger, E (2017)
  • The Abl pathway bifurcates to balance Enabled and Rac signaling in axon patterning in Drosophila
  • Development, 144(3), 487-498
  • 8) Smith-Trunova, S., Prithviraj, R., Spurrier, J., Kuzina, I., Gu, Q. and Giniger, E (2015)
  • Cdk5 regulates developmental remodeling of mushroom body neurons in Drosophila
  • Dev Dynamics, 244, 1550-1563
  • 9) Kannan, R., Kuzina, I., Wincovitch, S., Nowotarski, S.H., and Giniger, E (2014)
  • The Abl/Enabled signaling pathway regulates Golgi architecture in Drosophila photoreceptor neurons
  • Mol Biol of the Cell, 25, 2993- 3005.
  • 10) Giniger, E (2012)
  • Notch signaling and neural connectivity
  • Curr Opin Genet and Devel, 22, 339-346.
  • 11) 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
  • 12) 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
  • 13) 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
  • 14) Le Gall, M., DeMattei, C. and Giniger, E. (2008)
  • Molecular separation of two signaling pathways for the receptor, Notch
  • Dev. Biol, 313, 556-567
  • 15) 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
  • 16) 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
  • 17) 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
  • 18) 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
  • 19) Bothwell, M. and Giniger, E. (2000)
  • Alzheimer's Disease: Neurodevelopment Converges with Neurodegeneration
  • Cell , 102, 271-273
  • 20) 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
  • 21) Ostrander, E. A. and Giniger, E. (1999)
  • Let sleeping dogs lie?
  • Nature Genetics , 23, 3-4
  • 22) 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
  • 23) Fuerstenberg, S. M. and Giniger, E. (1998)
  • Multiple roles for Notch in Drosophila myogenesis
  • Dev. Biol, 201, 66-77
  • 24) 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
  • 25) 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
  • 26) 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
  • 27) 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
  • 28) 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
  • 29) 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
  • 30) Giniger, E. and Ptashne, M. (1988)
  • Cooperative binding of the yeast transcriptional activator, GAL4
  • Proc Natl Acad Sci, USA , 85, 382-386
  • 31) Giniger, E. (1988)
  • A role for abl in Notch signaling
  • Neuron , 20, 667-681
  • 32) Fischer, J. A., Giniger, E., Maniatis, T. and Ptashne, M. (1988)
  • GAL4 activates transcription in Drosophila.
  • Nature , 332, 853-856
  • 33) 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
  • 34) Giniger, E., Varnum, S. M. and Ptashne, M. (1985)
  • Specific DNA binding of GAL4, a positive regulatory protein of yeast.
  • Cell , 40, 767-774
  • 35) 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
  • 36) 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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