BBS Faculty Member - David Van Vactor

David Van Vactor

Department of Cell Biology

Harvard Medical School
LHRRB Building, Room 409
240 Longwood Avenue
Boston, MA 02115
Tel: 617-432-2195
Fax: 617-432-2808
Email: davie@hms.harvard.edu
Lab Members: 6 postdoctoral fellows, 1 graduate student, 2 research assistants, 2 undergraduates
Visit my lab page here.



Neuronal growth cones face a complicated embryonic landscape with many types of extracellular guidance information. Although much progress has been made by many labs in identifying both secreted and cell surface guidance factors and their receptors, much less is known about the intracellular machinery that translates this information into specific and reproducible guidance behavior. Since this is fundamentally a problem of leading edge motility and cell movement, we have concentrated part of our effort on understanding the proteins that control cytoskeletal dynamics in the growth cone. Our ultimate goal is to understand the signaling pathways, from cell surface to actin polymer network to microtubule arrays, that growth cones use to accurately interpret guidance information and execute directional outgrowth. After a growth cone reaches the appropriate destination, it must construct a specialized cellular junction or synapse in order to communicate with its target cell in a functional circuit. Our studies of the LAR receptor phosphatase led us to the discovery that the LAR pathway regulates synaptic growth and the morphogenesis of the active zone – a structure that orchestrates neurotransmitter release at chemical synapses. We have defined factors upstream and downstream of LAR in this context, and the machinery appears to be highly conserved. In addition, we find that this pathway is under the regulation of genes linked to human mental retardation, suggesting a molecular model for disorders of cognitive dysfunction.

Tyrosine Kinase Coordination of Actin and Microtubule Cytoskeletal Dynamics in the Axon
The accurate navigation of axons along stereotyped pathways in vivo requires coordination of the key effector systems that control growth cone motility. The Abl family of conserved intracellular tyrosine kinases act downstream of multiple classes of axon guidance factor receptors. Genetic screens for Abl effectors in Drosophila identified the both actin regulatory factors and the microtubule plus-tip interacting protein (MT+TIP) CLASP as a protein required for Abl function in vivo. Our subsequent biochemical and functional studies showed that CLASP associates with and is phosophorylated by CLASP in mammalian cells, suggesting conservation in the guidance machinery. We have used genetic and proteomic tools to define a network of functional partners for CLASP, and find not only additional MT+TIPs, but also MT-actin cross-linking factors suggesting that CLASP and Abl are involved in the coordination of the two major polymer systems.

The Formation and Growth of Functional Synaptic Connections
After a growth cone reaches the appropriate destination, it must construct a specialized cellular junction or synapse in order to communicate with its target cell in a functional circuit. Our studies of the LAR receptor phosphatase led us to the discovery that the LAR pathway regulates synaptic growth and the morphogenesis of the active zone – a structure that orchestrates neurotransmitter release at chemical synapses. We have defined factors upstream and downstream of LAR in this context, and the machinery appears to be highly conserved. Upstream, LAR interacts with synaptic heparan sulfate proteoglycans that control distinct aspects of synapse morphogenesis or function. Downstream, LAR activity is mediated by a pathway linking the phosphatase cytoskeletal remodeling. In addition, we find that this pathway is under the regulation of genes linked to human mental retardation, suggesting a molecular model for disorders of cognitive dysfunction.

MicroRNA Regulation of Synapse Specificity and Morphogenesis
Much has been learned about the signaling pathways and networks of proteins that function together to build and modulate synaptic connections. This rich molecular landscape is under the control of multiple classes of regulatory factors. MicroRNA are versatile posttranscriptional regulators capable of tuning levels of gene expression across a large number of target genes. Through genetic screens in Drosophila, we have discovered that synapse formation and growth are controlled by the conserved microRNA miR-8, a factor that orchestrates different stages of synapse development through distinct sets of direct and indirect targets. Having recently created a means of selectively inhibiting the function of any microRNA with spatio-temporal precision in vivo, we are now equipped to survey the functions of all microRNAs in Drosophila in many aspects of neural development, connectivity, and behavior.



Last Update: 8/28/2013



Publications

For a complete listing of publications click here.

 


 

Lowery LA, Van Vactor D. The trip of the tip: understanding the growth cone machinery. Nat Rev Mol Cell Biol. 2009 May;10(5):332-43. doi: 10.1038/nrm2679. Epub 2009 Apr 17. Review. PubMed PMID: 19373241; PubMed Central PMCID: PMC2714171.

Loya CM, Lu CS, Van Vactor D, Fulga TA. Transgenic microRNA inhibition with spatiotemporal specificity in intact organisms. Nat Methods. 2009 Dec;6(12):897-903. doi: 10.1038/nmeth.1402. Epub 2009 Nov 15. PubMed PMID: 19915559; PubMed Central PMCID: PMC3183579.

McNeill E, Van Vactor D. MicroRNAs shape the neuronal landscape. Neuron. 2012 Aug 9;75(3):363-79. doi: 10.1016/j.neuron.2012.07.005. Review. PubMed PMID:
22884321; PubMed Central PMCID: PMC3441179.

Long JB, Bagonis M, Lowery LA, Lee H, Danuser G, Van Vactor D. Multiparametric Analysis of CLASP-Interacting Protein Functions during Interphase Microtubule Dynamics. Mol Cell Biol. 2013 Apr;33(8):1528-45. doi: 10.1128/MCB.01442-12. Epub 2013 Feb 4. PubMed PMID: 23382075.



© 2013 by the President and Fellows of Harvard College