Molecular and Cellular Neural Development
Our lab is interested in understanding the cellular and molecular mechanisms that drive the formation of the nervous system and how those steps can go awry to cause neural developmental disorders.
Our focus is on the development of the peripheral nervous system (PNS) because it derives from a fascinating cell population, the neural crest, which migrates throughout the embryo to give rise to the various components of the PNS. We want to understand the intracellular and extracellular cues that mediate the migration and differentiation of the distinct cell types that comprise the PNS. In particular we are interested in how the different classes of sensory neurons in the dorsal root ganglion: nociceptors, thermoreceptors, mechanoreceptors and proprioceptors differentiate from the neural crest, and the cues that distinguish neural crest cells destined for the dorsal root ganglion (DRG) vs. the sympathetic ganglion. Our model system for these studies is the avian (chick and quail). 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. From these studies we (and others) have characterized the different waves of migrating neural crest, their migration pathways, and identified distinct subpopulations of progenitor cells that give rise to the different classes of sensory neurons in the DRG.
With this knowledge in hand, we are also investigating which of these steps are disrupted to cause the human hereditary sensory and autonomic neuropathy, Familial Dysautonomia. This developmental disorder is marked by devastation of the autonomic nervous system and decreased pain and temperature sensation and results from a mutation in the gene Ikbkap. To this end, we have generated two mouse models for Familial Dysautonomia in which we have deleted Ikbkap from either the neural crest, or from CNS neurons to distinguish the contribution of each cell type to the human disorder. We are now currently investigating the phenotype of both mouse lines and finding they recapitulate major hallmarks of the human disease. We are also very interested in determining the function of Ikbkap in the developing nervous system to fully understand why this gene is required for normal neural development and function.
Publications via Google Scholar
George L, Chaverra M, Wolfe L, Thorne J, Close-Davis M, Eibs A, Riojas V, Grindeland A, Orr M, Carlson GA, Lefcort F. (2013). Familial dysautonomia model reveals Ikbkap deletion causes apoptosis of Pax3+ progenitors and peripheral neurons. PNAS. 110 (46), 18698-18703.
Kasemeier-Kulesa JC, Lefcort F, Kulesa PM. (2013). Dorsal migration and formation of the secondary, permanent chain of sympathetic ganglia as revealed by the confocal time-lapse analysis in chick. Autonomic Neuroscience. 177 (2), 315-315.
Kulesa P, Kasemeier-Kulesa JC, Lefcort F. (2013). Dynamic Formation of the Chick Sympathetic Ganglia. FASEB JOURNAL 27.
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).