Aaron DiAntonio, MD, PhD
Alan A and Edith L Wolff Professor of Developmental Biology
- Phone: 314-362-9925
- Email: email@example.com
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:
- 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.
- 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.
- Synaptic function: A 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.
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
AAAS Fellow, American Academy for the Advancement of Science, 2020
Javits Neuroscience Award, NIH, 2020
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
- Ko, K.W., Milbrandt, J., and DiAntonio, A. (2020) SARM1 acts downstream of neuroinflammatory and necroptotic signaling to induce axon degeneration. J.C.B. 219: e201912047.
- Li, H., Russo, A., and DiAntonio, A. (2019) SIK3 suppresses neuronal hyperexcitability by regulating the glial capacity to buffer K+ and water. JCB 218: 4017-4029
- Sasaki, Y., Engber, T.M., Hughes, R.O., Figley, M.D., Wu, T., Bosanac, T., Devraj, R., Milbrandt, J., and DiAntonio, A. (2020) cADPR is a gene dosage-sensitive biomarker of SARM1 activity in healthy, compromised, and degenerating axons. Exp. Neurology 329: 113252.
- Russo, A. and DiAntonio, A. (2019) Wnd/DLK is a critical target of FMRP responsible for neurodevelopmental and behavior defects in the Drosophila model of Fragile X Syndrome. Cell Reports 28: 2581-2593.
- Shin, J.E., Ha, H., Kim, Y.K., Cho, Y., and DiAntonio, A. (2019) DLK regulates a distinctive transcriptional regeneration program after peripheral nerve injury. Neurobiology of Disease 127: 178-192.
- Geisler, S., Huang, S., Strickland, A., Doan, R.A., Summers, D.W., Mao, X., DiAntonio, A., and Milbrandt, J. (2019) Gene therapy targeting SARM1 blocks pathological axon degeneration in mice. Journal of Experimental Medicine 216: 294-303. PMC6363435
- Karney-Grobe, S., Russo, A., Frey, E., Milbrandt, J., and DiAntonio, A. (2018) HSP90 is a chaperone for DLK and is required for axon injury signaling. P.N.A.S. 115: E9899-E9908. PMC6196532
- Summers, D.W., Milbrandt, J., and DiAntonio, A. (2018) Palmitoylation enables MAPK-dependent proteostasis of axon survival factors. P.N.A.S. 115: E8746-E8754. PMC6140512
- Essuman, K., Summers, D.W., Sasaki, Y., Mao X., Yim A.K.Y., DiAntonio, A., Milbrandt, J. (2018) TIR Domain Proteins Are an Ancient Family of NAD+ Consuming Enzymes. Current Biology 28: 421-430. PMC5802418
- 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.