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Molecular Biology and Genetics
Otolaryngology-Head & Neck Surgery
855 N. Wolfe Street
Baltimore MD 21205
Molecular mechanisms of signal transduction and neurogenesis in the olfactory system
The mammalian olfactory system provides an excellent model to study two of the important questions in molecular neurobiology. The continual replacement of olfactory receptor neurons mimics many aspects of neuronal differentiation and development in the brain. The olfactory system, therefore, provides a unique opportunity to observe processes in adults that, in other neuronal systems, only occur in the embryo. Additionally, the mammalian olfactory system has the remarkable ability to detect a wide variety of odorant molecules with high sensitivity and specificity. Olfactory acuity likely results from the contributions at the levels of anatomy, cellular structure and organization, biochemistry, genetics and neuronal connectivity. My laboratory uses biochemical and molecular genetic techniques to examine the mechanisms underlying development in the olfactory system, as well as the processes responsible for odorant detection. One major focus of the laboratory is to characterize the cells responsible for ongoing neurogenesis in the olfactory epithelium. Our recent work suggests that a highly quiescent stem cell resides in the neuroepithelium and transiently proliferates in response to tissue damage and neuronal loss. There appear to be negative feedback mechanisms that maintain homeostatic control of neuron number and replacement. Additional mechanisms involving extrinsic growth control factors serve to modulate proliferation and differentiation in progenitor cells through transcriptional regulators that we have identified in the laboratory. A second major effort in the laboratory focuses on the mechanisms that determine the patterns of expression of individual odorant receptor genes within the epithelium and the mechanism that control the pathways and eventual target cells chosen by those receptor neurons. We have identified transcription factors that likely coordinate the expression of key components in the outgrowth of neurons in mammals and C elegans. We have studied the mammalian olfactory system to elucidate the contributions of biochemistry, genetics and neural connectivity to sensitivity and specificity in olfactory signal transduction and the elaboration of the olfactory cilia, the sensory organelle in this tissue. We continue to characterize the molecular components of the second messenger pathways in olfactory and non-olfactory system. Finally, the molecular cloning of components of the olfactory signal transduction cascade, especially the receptor protein genes, has provided the essential tools to examine the processes which define the connections between the olfactory neuroepithelium and the brain. Combined with other approaches in our laboratory, we hope to elucidate the principles of olfactory coding and odorant perception.
Cheng LE and Reed R.R. (2007) Zfp423/OAZ participates in a developmental switch during olfactory neurogenesis. Neuron 54 547-57.
Leung C.T., Coulombe P.A. and Reed R.R. (2007) Contribution of Olfactory Neural Stem Cells to Tissue Maintenance and Regeneration. Nature Neurosci. 10 720-6.
Lewcock JW, Reed R.R. (2004) A feedback mechanism regulates monoallelic odorant receptor expression. Proc Natl Acad Sci U S A. 101(4): 1069-74.
Kulaga, H.M., Leitch, C.C., Eichers, E.R., Badabo, J.L., Lesemann, A., Hill, J., Hoskins, J.R., Beales, P.L., Reed, R.R. and Katsanis, N. (2004) Mutations in BBS proteins cause anosmia in humans and defects in olfactory cilia structure and function in the mouse. Nature Genetics 36(9): 994-8.