McClintock Lab: Neurogenomics of Olfaction and Neural Regeneration
Louis Boyarsky Professor of Physiology, University of Kentucky
- Yelena Alimova
- Naazneen Khan, Ph.D.
Olfactory physiology and neurogenesis
The olfactory system does two unique things: It detects odors and it continuously replaces injured neurons even in adults by activating local progenitor basal cells. We investigate the molecular physiology of both of these processes. We use physiological genomics techniques, such as microarrays, to observe system-wide effects and then use techniques focused on individual processes or genes, such as targeted gene deletion, electrophysiology, biochemistry, and anatomy to plumb the depths of regulatory networks of proteins controlling function.
Mouse odorant receptors: Gene expression and function. Our studies of the odorant receptors (ORs) involve both the control of their expression, especially by transcription factors (McIntyre et al., 2008; Zhang et al., 2016), and the study of OR function. We are particularly interested in the in vivo identification of the ORs that respond to an odor. To make these functional studies possible, we invented the Kentucky assay, and are now able to identify ORs responsive in vivo to any odor (McClintock et al., 2014; de March et al., 2020). Our work on activity-dependent genes contributed greatly to these advances (Fischl et al., 2014). We are taking advantage of the Kentucky assay to study the pharmacology of the odorant receptors and to develop pharmacological tools to manipulate odor perception. Manipulating odor perception has translational applications in several areas of human health.
Mouse olfactory sensory neurons: Gene expression and phenotype. Our studies of the membrane trafficking of odorant receptors indicated the presence of olfactory-specific receptor trafficking proteins (Gimelbrant et al., 1999; 2001) that led to investigation of gene expression in purified olfactory sensory neurons. A small-scale analysis yielded new cell-type specific markers not only for mature olfactory sensory neurons, but also for sustentacular cells and respiratory epithelium (Yu et al., 2005). More comprehensive analyses coupled with extensive in situ hybridization data identified the majority of the many thousands of genes expressed by mature and immature olfactory sensory neurons (Sammeta et al., 2007; Nickell et al., 2012; Heron et al., 2013). These data predict not only candidate genes for known functions but also entire biological processes that are active in olfactory sensory neurons. Excel files of these data are available (click here to download the data).
Mouse olfactory neurogenesis: We have also investigated the molecular changes that underlie adult olfactory neurogenesis, finding that the major molecular changes mirror the temporal changes in cell proliferation and phenotype that occur as the mature neurons die and are subsequently replaced (Shetty et al., 2005; Heron et al., 2013). Furthermore, by coupling these data with our detailed knowledge of gene expression in mature versus immature olfactory sensory neurons, we were able to determine the timing of onset of many biological processes during olfactory neurogenesis. We also found that the molecular changes that drive adult olfactory neurogenesis are highly similar to embryonic neurogenesis in the brain.
Mouse olfactory cilia genes: Cilia are critical to the odor detection by olfactory sensory neurons, and to developmental and signaling functions in other organ systems. Using bioinformatics methods based on tissue and cell expression patterns, we have predicted new mouse cilia genes (McClintock et al., 2008). In general, these genes are highly expressed in olfactory sensory neurons (click here to download the data).
Lobster olfaction: Molecular physiology and neurogenesis. Lobsters provide several advantages for investigating the physiology and biochemistry of olfactory transduction. We have cloned and characterized several components of the dual olfactory transduction pathways used by lobsters (McClintock et al., 1997; Xu et al., 1997; 1998; 1999; Xu and McClintock, 1999). Our studies of gene expression in the lobster olfactory organ have more recently expanded to include the identification of olfactory-specific mRNAs and of genes responsive to stimuli that induce adult neurogenesis (Hollins et al., 2003; Stoss et al., 2004; Stepanyan et al., 2005). To futher extend this avenue of investigation, we collaborated with the laboratories of Barry Ache (University of Florida) and Charles Derby (Georgia State University) to clone and sequence more than 5,000 cDNAs from a subtracted EST library made from the mature zone of the olfactory organ. These sequences and the BLAST searches used to identify them are available for downloading (click here to download the data).