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Lorene Lanier, Ph.D. Assistant Professor, Department of Neuroscience E-mail: lanie002@umn.edu

Research Interests:

Developing neurons extend long processes, called axons and dendrites, that must navigate through the surrounding tissue in order to reach their final targets. This navigation is accomplished by the growth cone, a highly dynamic structure at the end of developing axons and dendrites. There are literally hundreds of extracellular guidance molecules that can trigger multiple intracellular signaling pathways. The fact that the growth cone can integrate all this information and generate a coordinated response (e.g. grow in this/that direction), suggests that there is a convergence point(s) downstream of the signaling pathways. Because growth cone motility is critically dependent on dynamic changes in the actin cytoskeleton, we believe that actin binding/regulatory proteins may be the ultimate convergence point downstream of growth cone guidance signals.

In the past few years, much of the work on the actin cytoskeleton has focused on motile systems such as intracellular pathogens and fibroblasts. It has been widely assumed that the paradigms developed from these systems would be directly transferable to neuronal growth cones. In fact, we have recently shown that the mechanisms that regulate growth cone motility are distinct from those that regulate other types of actin-based motility, even though many of the same proteins are involved. Specifically, we have shown that one group of actin-binding proteins, the Arp2/3 complex, has a very different effect in growth cones and fibroblasts. In fibroblasts, Arp2/3 is enriched at the cell periphery/leading edge and blocking Arp2/3 function inhibits motility. In contrast, we were surprised to discover that Arp2/3 is enriched in the central, not the peripheral, region of the growth cone (see figure below) and that inhibition of Arp2/3 enhances growth cone motility. Moreover, we have recently shown that inhibition of Arp2/3 can alter growth cone response to guidance signals, suggesting that actin-binding proteins such as Arp2/3 may indeed serve as convergence points downstream of guidance signals. Future projects in the lab will focus on elucidating the molecular function of Arp2/3 and other actin-binding proteins in the growth cone. Ultimately, we hope to use targeted manipulation of cytoskeletal dynamics as a tool to direct neuronal development and regeneration.

Selected Publications:

Ikin AF, Sabo SL, Lanier LM, Buxbaum JD. A macromolecular complex involving the amyloid precursor protein (APP) and the cytosolic adapter FE65 is a negative regulator of axon branching. Mol Cell Neurosci. 2007 May;35(1):57-63. Epub 2007 Feb 8.

Díaz-Martínez LA, Giménez-Abián JF, Azuma Y, Guacci V, Giménez-Martín G, Lanier LM, Clarke DJ. PIASgamma is required for faithful chromosome segregation in human cells. PLoS ONE. 2006 Dec 20;1:e53.

Lebrand, C., Dent, E. W., Strasser, G. A., Lanier, L. M., Krause, M., Svitkina, T. M., Borisy, G. G., and Gertler, F. B. (2004). Critical role of Ena/VASP proteins for filopodia formation in neurons and in function downstream of netrin-1. Neuron 42, 37 -49.

Strasser, G. A., Abdul Rahim, N., VanderWall, K. A., Gertler, F. B., and Lanier, L. M. (2004). Arp2/3 is a Negative Regulator of Growth Cone Translocation. Neuron 43 (1) 89-94.

Lanier, L. M. and F. B. Gertler (2000). Actin cytoskeleton: thinking globally, actin' locally. Curr Biol 10(18): R655-7.

Lambrechts, A., A. V. Kwiatkowski, L. M. Lanier, J. E. Bear, J. Vandekerckhove, C. Ampe and F. B. Gertler (2000). cAMP-dependent protein kinase phosphorylation of EVL, a Mena/VASP relative, regulates its interaction with actin and SH3 domains. J Biol Chem 275(46): 36143-51.

Lanier, L. M. and F. B. Gertler (2000). From Abl to actin: Abl tyrosine kinase and associated proteins in growth cone motility. Curr Opin Neurobiol 10(1): 80-7.

Zukerberg, L. R., G. N. Patrick, M. Nikolic, S. Humbert, C. L. Wu, L. M. Lanier, F. B. Gertler, M. Vidal, R. A. Van Etten and L. H. Tsai (2000). Cables links Cdk5 and c-Abl and facilitates Cdk5 tyrosine phosphorylation, kinase upregulation, and neurite outgrowth. Neuron 26(3): 633-46.

Current Graduate Students:

Marcela Maldonado (Neuroscience, University of Minnesota).

Rachel Penrod (Neuroscience, University of Minnesota).