The McKnight lab studies biological regulation with special interest in connections between the metabolic state of cells and their physiological output as dictated by changes in gene expression, intracellular signaling, cell division and neuronal activity. It is our hypothesis that cells can exist in a continum of metabolic states varying from energy charged to energy depleted, and that this charge state is intimately interconnected with regulatory pathways that dictate what what cells actually do. We seek to identify regulatory proteins involved in the control of gene expression, or the control of intracellular signaling, that can directly bind to metabolites that fluctuate in abundance as a function of energy charge state. For example, if a cell has exhauseted its supply of ATP, and suffers a higher than normal ratio of AMP to ATP - how is this information processed to circumscribe the biological or physiological activity of that cell. Likewise, if a cell has exhausted its supply of reducing equivalents in the form of NADH or NADPH, and therefore has reduced ratios of NADH to NAD - and NADPH to NADP - how might these changes be interpreted by the cell to regulate its physiological output. It is our hypothesis that the metabolic state of a cell changes as a function of the circadian cycle, as well as the sleep:wake cycle. We further believe that the metabolic state of neurons withing the central nervous system is ultimately involved in controlling the birth of new neurons in a region of the mouse brain called the dentate gyrus. In a more limited sense, the McKnight lab has discovered two transcription factors - designated neuronal PAS domain 1 (NPAS1) and NPAS3 that reciprocally regulate adult neurogenesis in the adult mouse brain. Mice lacking the NPAS1 transcription factor produce more neurons than normal, whereas mice lacking the NPAS3 transcription factor produce fewer neurons than normal. Through an understanding of the balance of these opposing transcription factors we have come to view adult neurogenesis in the dentate gyrus as a "signpost" of brain activity. Neurogenesis is robust in the brain tissue of mice that are active and healthy. By contrast, the level of adult neurogenesis is substantially reduced in animals deprived of an enriched environment. By use of this neurogenesis "signpost" we have conducted a drug screen to search for small synthetic compounds that are capable of stimulating adult neurogenesis. Among 1,000 drugs screened to date, 8 have been found to be capable of stimulating adult neurogenesis. Current efforts are devoted to the discovery of the modes of action of the 8 pro-neurogenic chemicals discovered in the screen.
RESEARCH INTERESTS
metabolic rhythms
circadian rhythm
gene regulation
intracellular signaling
neurogenesis
RECENT PUBLICATIONS
Chen, Odstrcil, Tu and McKnight, "Restriction of DNA Replication to the Reductive Phase of the Metabolic Cycle Protects Genome Integrity." Science, 316:1916-1919., 2007
Tu and McKnight, "Metabolic Cycles as an Underlying Basis of Biological Oscillations" Nature Reviews of Molecular and Cell Biology, 7:696-701, 2006
Tu, Kudlicki, Rowicka and McKnight, "Logic of the Yeast Metabolic Cycle: Temporal Compartmentalization of Cellular Processes."
Pieper, Wu, Han, Estill, Dang, Wu, Reece-Fincanon, Dudley, Richardson, Brat and McKnight, "The Neuronal PAS Domain Protein 3 Transcription Factor Controls FGF-mediated Adult Hippocampal Neurogenesis in Mice." PNAS, 102:14,052-14,057, 2005
Erbel-Sieler, Dudley, Zhou, Wu, Estill, Han, Diaz-Arrastia, Brunskill, Potter and McKnight, "Behavioral and Regulatory Abnormalities in Mice Deficient in the NPAS1 and NPAS3 Transcription Factors" PNAS, 101:13,648-13,653, 2004
SIGNIFICANT PUBLICATIONS
Harland, R.M., Weintraub, H., and McKnight, S.L., "Transcription of DNA Injected into Xenopus Oocytes is Influenced by Template Topology" Nature, 301:38-43, 1982
McKnight, S.L. and Kingsbury, R., "Transcriptional Control Signals of a Eukaryotic Protein-Coding Gene" Science, 217:316-325, 1982
Umek, R.M., Friedman, A. and McKnight, S.L., "CCAAT/Enhancer Binding Protein: A Component of a Different Switch" Science, 251:288-292, 1991
Landschulz, W.H., Johnson, P.F., and McKnight, S.L., "The Leucine Zipper: A Hypothetical Structure Common to a New Class of DNA Binding Proteins" Science, 240:1759-1764, 1988
Hou, J., Henzel, W.H., Ho, T.C., Brasseur, M., and McKnight, S.L., "An Interleukin-4-Induced Transcription Factor: IL-4 Stat." Science, 265:1701-1706, 1994
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