Molecular and Cellular Neural Development
Our lab is interested in understanding the cellular and molecular mechanisms that drive the formation of the nervous system.
Specifically, we are interested in the mechanisms mediating the sequence of distinct cellular behaviors integral to tissue morphogenesis and embryonic development. Our approach has been to study molecular mechanisms in the context of intercellular interactions and interactions of cells with their environment. Thus we are interested in how extracellular signals located in the environment integrate with intrinsic intracellular cues to ultimately regulate the proliferation and differentiation of the discrete cell types that comprise the nervous system.
Our model system is the avian (chick) peripheral nervous system. This system is compelling because of the wealth of information already established about how the neural crest give rise to the PNS, and because of the ease of conducting in ovo gain-and-loss of function experiments. Lastly, this system is attractive because we can use live time lapse imaging to observe neural crest cells moving in their normal environments.
With this system we have two had two major lines of experimentation. One is to understand the function of receptor tyrosine kinases and their ligands in the genesis and differentiation of sensory neurons in a major neural crest derivative, the dorsal root ganglia (DRG). To this end we have studied the role of the neurotrophin receptors (Trks), neuregulins, and ALK in the developing PNS. Our second goal has been to use live time lapse imaging to elucidate the cellular mechanisms that drive the formation of the peripheral nervous system (PNS).
Our goals for the next few years are to combine molecular manipulations with live imaging to understand the relative role of pre-patterning (intrinsic) cues vs. environmental cues in specifying the fate of migrating neural crest cells. Specifically, we will continue to focus on mechanisms regulating the behavior of crest cells that stop to form the DRG vs. those that continue to migrate to form the sympathetics. We are also identifying classes of progenitor cells in the DRG and how they give rise to distinct subsets of sensory neurons (George et al., manuscript in preparation). Using GFP-labeled reporter constructs for ngns and notch, we will image neuronal differentiation in the DRG and be able to correlate differentiation with cell behavior in real time. We are also very interested in identifying the cues are that induce cells in the primary chain of sympathetics to reorient dorsally and undergo a second dorsal migration to form the permanent secondary chain of sympathetics and are currently investigating potential chemotropic mechanisms that regulate that process in conjunction with live imaging.
Publications via Google Scholar
Hunnicutt BJ, Chaverra M, George L, Lefcort F. (2012). IKAP/Elp1 is required in vivo for neurogenesis and neuronal survival, but not for neural crest migration. PLoS One. 7(2):e32050.
George, L., J. Kasemeier-Kulesa, B.R. Nelson, and F. Lefcort. (2010). Patterned assembly and neurogenesis in the avian dorsal root ganglion. J. Comp. Neurol. 518(4):405-22. (Cover photo).
Kasemeier-Kulesa, J., P.M. Kulesa, and F. Lefcort (2010). CXCR4 controls ventral migration of sympathetic precursor cells. Journal of Neuroscience. 30(39):13078-88.
Kulesa PM, Lefcort F, Kasemeier-Kulesa JC. (2009). The migration of autonomic precursor cells in the embryo. Auton Neurosci. 151(1):3-9.
George, L., M. Chaverra, V. Todd, R. Lansford and Lefcort, F. (2007). Nociceptive sensory neurons derive from contralaterally migrating, fate restricted neural crest cells. Nature Neuroscience 10 (10): 1287-93.
Kasemeier-Kulesa, J.C., F. Lefcort, and P. M. Kulesa. (2007). Sagittal explant culture for 3D confocal time-lapse analysis of chick peripheral nervous system formation. CSH Protocols. Cold Spring Harbor Labs Press.
Lefcort, F. and George, L. (2007). Neural crest cell fate: to be or not to be prespecified. Cell Adhesion and Migration, 1(4): 199-201.
Hapner, S.J., Chaverra, M., Nielson, K.M., Esper, R., Loeb, J. and Lefcort, F. (2006). NT- 3 and CNTF exert dose-dependent, pleiotropic effects on cells in the immature dorsal root ganglion: Neuregulin-mediated proliferation of progenitor cells and neuronal differentiation. Developmental Biology 297(1):182-97.
Hurley, S., Douglas Clary, Valerie Copie and Lefcort, F. (2006). Anaplastic lymphoma kinase is dynamically expressed on subsets of motor neurons and in the peripheral nervous system. Journal of Comparative Neurology 495(2):202-12.
Kasemeier-Kulesa, J.C., Bradley, R., Pasquale, E., Lefcort, F. and Kulesa, P.M.(2006). Eph/ephrins and N-cadherin coordinate to control the pattern of sympathetic ganglia. Development. 133(24):4839-47.
Lefcort, Frances, Timothy O'Connor and Paul Kulesa. (2006). A comparative analysis of neural crest cell and axonal growth cone dynamics and behavior. In press in Intracellular Mechanisms in Neuritogenesis Editor, Ivan DeCurtis, Springer-Verlag.
Kasemeier-Kulesa, J.C., Paul M. Kulesa, and Lefcort, F. (2005). Imaging neural crest cell Dynamics during formation of dorsal root ganglia and sympathetic ganglia. Development, 132: pg. 235-245.
Kasemeier, J.C., F. Lefcort, S.E. Fraser and P. Kulesa. (2004). A novel sagittal slice explant technique for time-lapse imaging of the formation of the chick peripheral nervous system. Symposia; In Imaging in neuroscience and development (ed. R.Yuste and A. Konnerth). Cold Spring Harbor, NY. Cold Spring Harbor Press.
Nelson, B.R., K.Claes, M.Chaverra, V. Todd and Lefcort, F. (2004). NELL2 promotes Motor and sensory neuron differentiation and stimulates mitogenesis in DRG in vivo. Developmental Biology, 270: 322-335.
Nielson, K. ,Chaverra, M., Zigmond, R. and Lefcort, F. (2004). PACAP induces differentiation of DRG neurons: abrogation by NT-3 and CNTF. Molecular and Cellular Neuroscience, 25: 629-641.
Nelson, B.R. M. Sadhu, J. C. Kasemeier, L. W. Anderson, and F. Lefcort (2004). Identification of genes regulating sensory neuron genesis and differentiation in the avian dorsal root ganglia. 29(3):618-29. Developmental Dynamics.
BIOL 510: Topics In Neurobiology
WWAMI Medical Education Program:
MEDS 532: Nervous System
B.A. in Biology, Smith College, Northampton, Massachusetts, l982, cum laude.
Ph.D in Neurobiology, University of California, Berkeley, l988 (Dr. David R. Bentley, mentor).
Postdoctoral Fellow and Associate, University of California, San Francisco Howard Hughes Medical Institute and Department of Physiology, 10/88-8/94 (Dr. Louis F. Reichardt, mentor).