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RESEARCH QUESTIONS IN THE LEFCORT LABORATORY

A fundamental question in biology is how intrinsic, heritable cues and extrinsic, environmental signals interact to ultimately regulate cell identity. The sensory neurons of the mature dorsal root ganglia (DRG) are an extremely heterogeneous population of cells innervating such diverse targets as skin, muscle, viscera and subserving such discrete modalities as pain, temperature, touch, pressure, and proprioception. These neurons are also distinguished by trophic ependance on different members of the neurotrophin family of growth factors, synthesis of distinct classes of neurotransmitters, and stereotyped morphologies. Yet all of these (>20) functionally distinct subpopulations derive from the neural crest. DRG development proceeds by neural crest migration and aggregation to form the nascent DRG, proliferation of undefined populations of progenitor cells resident within the DRG, and subsequent differentiation of discrete classes of sensory neurons and glia. The complex yet experimentally accessible nature of the DRG has led to its status as an important model system for analysis of the cellular and molecular interactions that regulate the genesis and differentiation of discrete cell types. However, outstanding questions remain, such as whether there are discrete classes of progenitor cells resident within the DRG that give rise to subtypes of sensory neurons and what are the relative roles of inherited, intrinsic cues vs. extrinsic environmental signals in regulating the phenotype of individual sensory neurons? Thus, the long term objective of our work is to elucidate the cellular and molecular mechanisms that regulate the genesis and differentiation of sensory neurons in the developing dorsal root ganglion.

One major family of molecule on which our work is focused is the superfamily of receptor tyrosine kinases (RTKs); the rationale being that receptor tyrosine kinases when activated by their growth factor ligands exert profound activities on cell growth, proliferation and differentiation. The particular RTKs we are studying include the trk family of neurotrophin receptors, the tyro3/mer/axl family and ALK. Our goal is to determine the specific functions each of these receptors play during sensory neurogenesis in the DRG, using techniques in molecular and cell biology including in ovo electroporation of gain-of-function and dominant interfering receptor constructs. With these same techniques we are also investigating the function of a neural epidermal growth factor-like (NEL) during sensory neurogenesis and our preliminary data suggests Nel functions to promote neuronal differentiation in both the CNS and PNS.

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SELECTED PUBLICATIONS

Nelson BR, Matsuhashi S, and Lefcort F. (2002). Restricted neural epidermal growth factor-like like 2 (Nell2) expression during muscle and neuronal differentiation. Mech. Of Dev. In press.

Rifkin JT, Todd VJ, Anderson LW, and Lefcort F. (2000). Dynamic expression of neurotrophin receptors during sensory neuron genesis and differentiation. Developmental Biology, 227:465-480.

Oakley RA, Lefcort FB, Plouffe P, Ritter A, and Frank E. (2000). Neurotrophin-3 promotes the survival of a limited subpopulation of cutaneous sensory neurons. Developmental Biology, 224 (2):415-27.

Hapner SJ, Boeshore K, Large TH and Lefcort F. (1998). Neural differentiation promoted by truncated trkC in collaboration with p75NTR. Developmental Biology, 201: 90-100.

Oakley RA, Lefcort F, Clary D, Reichardt LF, Prevette D, Oppenheim R, and Frank E. (1997). Neurotrophin-3 promotes the survival and differentiation of muscle spindle afferents in the absence of peripheral targets. J.Neuroscience 17(11): 4262-74.

Lefcort F, Clary DO, Rusoff A, and LF Reichardt. (1996). Inhibition of the NT-3 receptor TrkC, early in chick embryogenesis, results in severe reductions in several neuronal subpopulations in the dorsal root ganglion. J.Neuroscience. 16 (11):3704-3713.