Aaron DiAntonio, M.D., Ph.D.
Alan A and Edith L Professor of Developmental Biology
Departments of Developmental Biology and Neurosciences
Our laboratory investigates molecular mechanisms that control the structure and function of neural circuits in development and disease. We combine genetic, molecular, neuroanatomical, and electrophysiological studies in both Drosophila and mouse to identify pathways required for the development, maintenance, and regeneration of axons and synapses. Our studies focus on three major areas:
1) Axonal degeneration in disease: Axonal degeneration is a common feature of many neurological diseases including hereditary neuropathies, diabetes, glaucoma, chemotherapy-induced neurotoxicity, and neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Axonal degeneration is an active process of self-destruction that appears to be naturally primed and waiting for a triggering stimulus that activates the execution phase. We identified the DLK/JNK MAP kinase pathway as the first intrinsic neuronal pathway that promotes axonal degeneration following injury. We are using genome-wide screens in both Drosophila and mice to identify the molecular mechanisms driving axonal degeneration. Identifying and characterizing components of the intrinsic axonal degeneration pathway has identified potential therapeutic targets for the many neurological diseases characterized by axonal degeneration.
2) Axonal regeneration in response to injury: Neuronal repair is greatly impaired by the failure of adult CNS neurons to regenerate axons lost to injury or disease. Remarkably, a prior preconditioning injury can activate an axonal growth program and promote axonal regeneration. We have recently demonstrated that the MAPKKK DLK is a key trigger that induces this preconditioning response. We are investigating the mechanisms by which this regenerative growth program can be activated in order to promote neuronal repair. Finally, we are using high-content automated screening approaches to undertake large-scale drug and RNAi screens in order to identify novel therapeutic candidates that induce axonal regeneration.
3) Synaptic function: Neurotransmitter is released from the presynaptic cell at specialized sites called active zones. Efficient synaptic transmission requires that active zones contain a normal complement of proteins, and that these specialized release sites be apposed to postsynaptic clusters of neurotransmitter receptor. Little is known of the molecular mechanisms that regulate the protein composition of active zones and ensure the alignment of neurotransmitter release and reception machinery. Using large-scale genetic screens in Drosophila we are uncovering the molecular mechanisms that form and maintain the active zone/receptor cluster dyad.
- Essuman K, Summers DW, Sasaki Y, Mao X, DiAntonio A, Milbrandt J. The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration. Neuron. 2017 Mar 22;93(6):1334-1343.e5.
- Walker, L.J., Summers, D.W., Sasaki, Y., Brace, E.J., Milbrandt, J., and DiAntonio, A. (2017) MAPK Signaling Promotes Axonal Degeneration by Speeding the Turnover of the Axonal Maintenance Factor NMNAT2. eLife 2017; 6:e22540.
- Geisler, S., Doan, R.A., Strickland, A., Huang, X., Milbrandt, J., and DiAntonio, A. (2016) Prevention of vincristine-induced peripheral neuropathy by genetic deletion of SARM1 in mice. Brain 139: 3092-3108.
- Sasaki, Y., Nakagawa, T., Mao X., DiAntonio, A., and Milbrandt, J. (2016) NMNAT1 inhibits axon degeneration via blockade of SARM1-mediated NAD+ depletion. eLife 2016; 5:e19749. PMC5063586
- Summers, D.W., Gibson, D.A., DiAntonio, A., and Milbrandt, J. (2016) SARM1-specific motifs in the TIR domain enable NAD+ loss and regulate injury-induced SARM1 activation. PNAS 113: E6271-E6280. PMC5068253
- Gerdts, J., Summers, D.W., Milbrandt, J., and DiAntonio, A. (2016) Axon self-destruction: new links among SARM1, MAPKs, and NAD+ metabolism. Neuron 89: 449-460. PMC4742785
- Bhattacharya, M., Geisler, S., Pittman, S., Doan, R., Weihl, C., Milbrandt, J., and DiAntonio, A. (2016) TMEM184b promotes axon degeneration and neuromuscular junction maintenance. J. Neuroscience 36: 4681-4689. PMC4846669
- Gerdts, J., Brace, E.J., Sasaki, Y., DiAntonio, A., and Milbrandt, J. (2015) Sarm1 activation triggers axon degeneration locally via NAD+ destruction. Science 348: 453-7. PMC4513950.
- Valakh, V., Frey, E., Babetto, E., Walker, L.J., and DiAntonio, A. (2015) Cytoskeletal disruption activates the DLK/JNK pathway, which promotes axonal regeneration and mimics a preconditioning injury. Neurobiology of Disease 77: 13-25. PMC4402261.
- Shin, J.E., Geisler, S., and DiAntonio, A. (2014) Dynamic regulation of SCG10 in regenerating axons after injury. Experimental Neurology 252: 1-11. PMC3947015
- Valakh, V., Walker, L.J., Skeath, J.B., and DiAntonio, A. (2013) Loss of the spectraplakin Short stop activates the DLK injury response pathway in Drosophila. J. Neuroscience 33: 17863-17873. PMC3818558
- Babetto, E., Beirowski, B., Russler, E.V., Milbrandt, J., and DiAntonio, A. (2013) The Phr1 ubiquitin ligase promotes injury-induced axon self-destruction. Cell Reports 5: 1422-1429. PMC3671584
- Shin, J.E., Miller, B.R., Babetto, E., Cho, Y., Sasaki, Y., Qayum, S., Russler, E.V., Cavalli, V., Milbrandt, J., and DiAntonio, A. (2012) SCG10 is a JNK target in the axonal degeneration pathway. P.N.A.S. 109: E3696-3705. PMC3535671
- Shin, J.E., Cho, Y., Beirowski, B., Milbrandt, J., Cavalli, V., and DiAntonio, A. (2012) Dual leucine zipper kinase is required for retrograde injury signaling and axonal regeneration. Neuron 74: 1015-1022. PMC3383631
- Kim, S., Naylor, S.A., and DiAntonio, A. (2012) Drosophila Golgi membrane protein Ema promotes autophagosomal growth and function. P.N.A.S. 109: E1072-1081. PMC3344964
- Graf, E.R., Daniels, R.W., Burgess, R.W., Schwarz, T., and DiAntonio, A. (2009) Rab3 Dynamically Controls Protein Composition at Active Zones. Neuron 64: 663-677. PMC2796257
- Miller, R.B., Press, C., Daniels, R.W., Sasaki, Y., Milbrandt, J., and DiAntonio, A. (2009) A DLK-dependent axon self-destruction program promotes Wallerian degeneration. Nature Neuro. 12: 387-389. PMC2696160
For a complete list of Dr. DiAntonio's publications, click here
Education and Training
- Professor of Department of Developmental Biology, Washington University School of Medicine, 2010-present
- Associate Professor Department of Developmental Biology, Washington University School of Medicine, 2005-present
- Assistant Professor Department of Developmental Biology, Washington University School of Medicine, 1999-2005
- Postdoctoral Fellow University of California at Berkeley, Department of Molecular and Cell Biology, 1995-1999. Postdoctoral Advisor: Dr. Corey Goodman
- Ph.D. Stanford University School of Medicine, Department of Molecular and Cellular Physiology, 1989-1995. Thesis Advisor: Dr. Thomas Schwarz
- M.D. Stanford University School of Medicine, 1989-1995
- M. Phil. Cambridge University, Biochemistry, 1989
- A.B. Harvard University, Biochemistry and Molecular Biology, 1984-1988
Honors and Awards
- Alan A. and Edith L. Wolff Professor of Developmental Biology, 2014
- Outstanding Faculty Mentor Award, Graduate Senate, Washington University, 2011
- Outstanding Faculty Mentor Award, Postdoctoral Society, Washington University, 2008
- Keck Distinguished Young Scholar, 2002-2007
- McKnight Scholar Award, 2002-2004
- Sloan Research Fellow, 2001-2003
- Edward Mallinckrodt, Jr. Foundation Award, 2000-2003
- Whitehall Foundation Award, 2000-2003
- Howard Hughes Medical Institute, Faculty Development Award, 2000-2002
- McDonnell Center Grant, 2000-2001
- Burroughs Wellcome Career Award in the Biomedical Sciences, 1998-2003
- Helen Hay Whitney Fellow 1996-1998
- Damon Runyon-Walter Winchell Fellow, 1996
- Medical Scientist Training Program Fellow, 1989-1995
- Hershel Smith Harvard Scholarship, Harvard College, 1988
- Phi Beta Kappa, Harvard College, 1988
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- Faculty Members
- Lilianna (Lila) Solnica-Krezel, Ph.D.
- Irving Boime, Ph.D.
- Angela Bowman, Ph.D.
- Aaron DiAntonio, M.D., Ph.D.
- Douglas F. Covey, Ph.D.
- Gregory A. Grant, Ph.D.
- Shin-ichiro Imai, M.D., Ph.D.
- S. Kerry Kornfeld, M.D., Ph.D
- Kristen Kroll, Ph.D.
- Craig Micchelli, Ph.D.
- Kelly Monk, Ph.D.
- Samantha A. Morris, Ph.D.
- Jeanne Nerbonne, Ph.D.
- David M. Ornitz, M.D., Ph.D.
- Zachary Pincus, Ph.D.
- Stacey Rentschler, M.D., Ph.D.
- John H. Russell, Ph.D.
- Andrew S. Yoo, Ph.D.
- Bo Zhang, Ph.D.
- Adjunct Faculty
- Joint Faculty Members
- Research Interests
- Emeritus Faculty
- Former Faculty
- Model Systems