Research Abstract:
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 and maintenance of axons and synapses. Our studies focus on three major areas:
1) 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.
2) Neural circuit formation and regeneration: In our studies of the morphological development of synapses we focus on a key negative regulator of synaptic growth, a protein called highwire in Drosophila. Highwire functions as a ubiquitin ligase and, using biochemical and genetic techniques, we are characterizing the synaptogenic signal pathways that it regulates. In addition, we have identified a single homolog of highwire in the mouse, termed Phr, which is highly expressed in the developing brain. We have generated constitutive and conditional knock-outs of Phr and we are characterizing it role in the formation, plasticity, and regeneration of neural circuits in the mammalian brain.
3) Axonal degeneration in response to injury: 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 have now identified the DLK/JNK MAP kinase pathway as the first intrinsic neuronal pathway that promotes axonal degeneration following injury. We are using molecular, genetic, and anatomical techniques in both Drosophila and mice to identify the molecular mechanisms driving axonal degeneration. Identifying and characterizing components of the intrinsic axonal degeneration pathway may identify potential therapeutic targets for the many neurological diseases characterized by axonal degeneration.
Selected Publications:
Miller RB, Press C, Daniels RW, Sasaki Y, Milbrandt J and DiAntonio A. A DLK-dependent axon self-destruction program promotes Wallerian degeneration. Nature Neuroscience 2009 12: 387-389.
Wairkar YP, Toda H, Mochizuki H, Furukubo-Tokunaga K, Tomoda T, DiAntonio A. Unc-51 Controls Active Zone Density and Protein Composition by Downregulating ERK Signaling. J. Neuroscience 2009 29: 517-528.
Bloom AJ, Miller BR, Sanes JR and DiAntonio A. The requirement for Phr1 in CNS axon tract formation reveals the corticostriatal boundary as a choice point for cortical axons. Genes and Development 2007 21: 2593-2606.
Collins CA, Wairkar YP, Johnson SL and DiAntonio A. Highwire restrains synaptic growth by attenuating a MAP kinase signal. Neuron 2006 51: 57-69.
Daniels RW, Collins CA, Chen K, Gelfand MV, Featherstone DE and DiAntonio A. A Single Vesicular Glutamate Transporter is Sufficient to Fill a Synaptic Vesicle. Neuron 2006 49: 11-16.
Last Updated: 06/16/2009 |