Delineate the molecular signaling mechanisms in model organisms that underlie axon guidance, growth cone function, and neuronal connectivity; understanding these pathways is critical for the development of new therapeutics that address CNS diseases and injuries.

The implications of Dr. Van Vactor’s lab’s research encompass a wide variety of unmet medical needs. Its studies on axon guidance and growth cone function are directly applicable to neuronal injury and regeneration, an area that has enormous commercial potential. The experiments on the signaling pathways involving the Drosophila orthologs of the human disease genes for fragile X syndrome (FMR1) and spinal muscular atrophy (SMN) are designed to identify new molecular targets for drug screening. There is a high degree of conservation with respect to human and Drosophila proteins, and Drosophila allows for relatively rapid genetic experimentation.
 

• Investigate cellular and biochemical signaling mechanisms, which are downstream from cell surface receptor activation, and following injury, that are responsible for synapse function, axon guidance, polarity, and neuron regeneration.
   
• Study developmental aspects of synapse formation and neuronal connectivity, using organisms such as Drosophila and C. elegans as model systems.
   
• Explore the role of the Abl tyrosine kinase and the cytoskeleton in transmitting signals emanating from cell surface receptors that are crucial for growth cone function, axon guidance, and cell division, with a focus on: dissecting the Abl-mediated signaling leading to microtubule perturbations via activation of cytoskeleton-associated porteins such as Orbit/CLASP and the actin-binding protein CAP; identifying proteins that associate with Orbit/CLASP; and studying the role of phosphorylation in this signaling pathway, with a particular emphasis on the LAR phosphatase and its control of synapse function.
   
• Research the signaling defects in Drosophila models for certain human diseases, such as Fragile X Mental Retardation (for example, the FMR1 gene) and the relationship of LAR signaling to FMR1 function, and Spinal Muscular Atrophy (SMA) caused by loss of the Survival of Motor Neuron (SMN) gene.
   
• Study the role of the LAR-associated heparan sulfate proteoglycans in the active zone and in synaptic function.
   
• Utilize high-resolution imaging technology, in combination with genetic studies, to gain insights into the relationship of synaptic proteins on neuronal morphogenesis.

Dr. Van Vactor’s lab uses model systems to explore the biochemical and cellular mechanisms that lead to axon guidance and synapse formation. The lab has extensively investigated signaling pathways emanating from the cell surface that are critical for proper axon guidance and targeting, employing a variety of approaches. Dr. Van Vactor is highly regarded in this field, and leading journals have asked him to provide commentary on new developments. His lab has recently reported on the role of specific proteoglycans in synapse development. Employing Drosophila as a model system, the lab found that the heparan sulfate proteoglycans syndecan and Dallylike are constituents of axons, and regulate both the growth of presynaptic terminals and the function of the active zone (that is, the specific areas beneath the plasma membrane of presynaptic neurons, where neurotransmitters accumulate in synaptic vesicles for subsequent release). The lab has implicated other proteins in axonal physiology, including the scaffolding protein Liprin-alpha that was found to affect the accumulation of synaptic vesicles at the active zone.

Dr. Van Vactor’s lab also made a breakthrough discovery regarding the role of the phosphatase LAR in regulating synapse form and function. Employing genetic screens, it determined that the Orbit/MAST microtubule-associated protein that is present in growth cones interacts with the Abl tyrosine kinase, and functions downstream of Abl to help coordinate the cytoskeleton dynamics that are essential for proper axon guidance.
 

Biological Mechanisms and Pathways

• Actin •
• Active zone •
• Axon guidance •
• Axonal transport •
• Cell migration •
• Cellular morphogenesis •
• Cytoskeleton •
• Developmental biology •
• Growth cone •
• Heparin sulfate proteoglycans •
• Microtubules •
• Neurobiology •
• Neuron •
• Neuronal cell biology •
• Presynaptic terminal •
• Signal transduction •
• Small GTPases •
• Synapse •
• Tyrosine kinase •
• Tyrosine phosphatase
•  

Disease Mechanisms

• Spinal Muscular Atrophy (SMA)
•  

Research Tools and Instrumentation

• Drosophila •
• Genetic screen
•  

Therapeutic Discovery Tools and Assays

• Drosophila
•