Cell Biology, Neurobiology & Anatomy

Margaret Wong-Riley, PhD Professor Department of Cell Biology, Neurobiology & Anatomy Medical College of Wisconsin 8701 Watertown Plank Road Milwaukee, WI 53226-0509 Phone: (414) 955-8467 FAX: (414) 955-6517 email: mwr@mcw.edu List of publications

Education:
PhD, Stanford University, Stanford, CA 1970
Postdoctoral, Postdoctoral, University of Wisconsin, Madison 1970-71
Lab of Neurophysiology, National Institutes of Health, 1972-73

Graduate Programs:
Program in Cell and Developmental Biology
Program in Neuroscience

Research Area: Coupling of neuronal activity and energy metabolism at the cellular and molecular levels. Cytochrome c oxidase as a metabolic marker for neuronal activity. Transcriptional regulation of cytochrome c oxidase and neurotransmitter receptors. Metabolic and neurochemical plasticity in the adult visual system. Critical period of neurochemical and metabolic development in brain stem respiratory neurons. Photobiomodulation of neurons functionally inactivated by toxins.

Our laboratory is interested in the ability of mature neurons to undergo plastic changes in response to altered functional demands. The central hypothesis is that neuronal activity and energy metabolism are tightly coupled; thus, the level of an energy-generating enzyme such as cytochrome c oxidase should correlate positively with the level of neuronal activity.

Since cytochrome c oxidase is a highly sensitive marker of neuronal activity, we are investigating its mechanism of regulation in the brain. We have found that the level of activity of this enzyme is regulated at its protein level, which, in turn, is regulated at its message and mitochondrial DNA levels. Moreover, the molecular activity, amount, and mRNA of this protein in the nervous system are under the tight control of neuronal activity. Cytochrome c oxidase is one of only four proteins in mammalian cells that are bigenomically encoded. Its largest three subunits are encoded in the mitochondrial genome and form the catalytic core of the enzyme, whereas the other ten subunits are encoded in the nuclear genome. Thus, it serves as an excellent model for studying bigenomic regulation of proteins. Neurons also pose a unique challenge in that mitochondrial genome in distal dendrites and axons can be far removed from the nucleus. The key question is, how do the two genomes coordinate their regulation to form a functional holoenzyme with one-to-one stoichiometry of 13 subunits? Does one genome play a more important role than the other? Are there transcription factors that can serve as bigenomic coordinators? Two candidates have been found: nuclear respiratory factors 1 and 2. These transcription factors directly activate all 10 nuclear-encoded cytochrome oxidase subunit genes as well as indirectly regulate the 3 mitochondrial-encoded subunit genes by activating other transcription factors, mitochondrial transcription factors A and B, which play important roles in regulating the transcription and replication of mitochondrial DNA. An important transcriptional co-activator of NRF-1 and NRF-2, known as PGC-1 (peroxisome proliferator-activated receptor gamma coactivator-1), is also under study. If neuronal activity is tightly coupled to energy metabolism, is it possible that the two processes are co-regulated at the transcriptional level? We are exploring transcription factors that may play such a dual role of regulating nor only cytochrome c oxidase, but neurotransmitter receptors as well in neurons.  Another research area is metabolic and neurochemical development of brain stem nuclei involved in respiratory control. The impetus for this research is that SIDS (Sudden Infant Death Syndrome) has its peak incidence not at birth, but months later, suggesting that there is a critical period of postnatal development when a seemingly normal infant may succumb to SIDS. In a rat model, we found a narrow window at the end of the second postnatal week when major neurochemical, metabolic, and ventilatory changes occur in normal animals, and when their response to hypoxia is at their weakest. The evidence of such a critical period of normal postnatal development has significant relevance to the understanding of SIDS. 

A third area of interest is the effect of near-infrared (NIR) light on energy metabolism in neurons. NIR has been known to promote wound healing, but its mechanism is poorly understood. It turns out that cytochrome c oxidase with copper centers is a key photoacceptor in the NIR range. When we treated cultured primary neurons intoxicated by various toxins with NIR, their energy levels returned toward normal and the incidence of apoptosis was drastically reduced. Currently, we are probing the mechanisms further with both in vivo and in vitro approaches. The goal is that NIR may rescue neurons partially damaged by diseases, such as Parkinson's Disease.

Our long-term goal is to unravel some of the molecular mechanisms related to metabolic and neurochemical abnormalities in human neurological and mitochondrial diseases.

Selected Publications:
	Liu Q, Wong-Riley MTT. Postnatal changes in the expressions of serotonin 1A, 1B, and 2A receptors in ten brain stem nuclei of the rat: implication for a sensitive period. Neuroscience. 2009 Oct 2. NIHMS155655.
	Liu Q, Fehring C, Lowry TF, Wong-Riley MTT. Postnatal development of metabolic rate during normoxia and acute hypoxia in rats: implication for a sensitive period. J Appl Physiol. 2009 Apr;106(4):1212-22. Epub 2008 Dec 31. PMID: 19118157.
	Dhar SS, Ongwijitwat S, Wong-Riley MT.  Chromosome conformation capture of all 13 genomic Loci in the transcriptional regulation of the multisubunit bigenomic cytochrome C oxidase in neurons. J Biol Chem. 2009 Jul 10;284(28):18644-50. Epub 2009 May 13.
	Dhar SS, Liang HL, Wong-Riley MT. Nuclear respiratory factor 1 co-regulates AMPA glutamate receptor subunit 2 and cytochrome c oxidase: tight coupling of glutamatergic transmission and energy metabolism in neurons. J Neurochem. 2009 Mar;108(6):1595-606. Epub 2009 Jan 23.
	Dhar SS, Wong-Riley MT. Coupling of energy metabolism and synaptic transmission at the transcriptional level: role of nuclear respiratory factor 1 in regulating both cytochrome c oxidase and NMDA glutamate receptor subunit genes. J Neurosci. 2009 Jan 14;29(2):483-92.
	Liu Q, Fehring C, Lowry TF, Wong-Riley MT. Postnatal development of metabolic rate during normoxia and acute hypoxia in rats: implication for a sensitive period. J Appl Physiol. 2009 Apr;106(4):1212-22. Epub 2008 Dec 31.
	Ying R, Liang HL, Whelan HT, Eells JT, Wong-Riley MT. Pretreatment with near-infrared light via light-emitting diode provides added benefit against rotenone- and MPP+-induced neurotoxicity. Brain Res. 2008 Dec 3;1243:167-73. Epub 2008 Sep 30.
	Wong-Riley MTT, HL Liang and S Ongwijitwat: Activity-dependent bigenomic transcriptional regulation of cytochrome c oxidase in neurons. In "Understanding Transcriptional Regulation by Neuronal Activity: To the Nucleus and Back". S. M. Dudek (ed.) New York, Springer Science, Chapter 11, pp. 209-228, 2008.
	Dhar SS, S Ongwijitwat and MTT Wong-Riley: Nuclear respiratory factor 1 regulates all ten nuclear-encoded subunits of cytochrome c oxidase in neurons. J Biol Chem, 283:3120-3129, 2008.
	Wong-Riley MTT and Q Liu: Neurochemical and physiological correlates of a critical period of respiratory development in the rat. Invited review. In Special Issue on “Neurochemistry of Respiratory Control”. D. McCrimmon, G. Mitchell and G. Alheid (eds.) Respiratory Physiology & Neurobiology, 2008 164(1-2):28-37.
	Liang HL, HT Whelan, JT Eells and MTT Wong-Riley: Near-infrared light via light-emitting diode treatment is therapeutic against rotenone- and MPP+-induced neurotoxicity. Neurosci 153:963-974, 2008.
	Liu Q, T Lowry and MTT Wong-Riley: Postnatal changes in ventilation during normoxia and acute hypoxia: implication for a sensitive period. J Physiol 577.3:957-970, 2006.
	Liang HL, H Whelan, J Eells, H Meng, E Buchmann, AM Lerch-Gaggl and M Wong-Riley: Photobiomodulation partially rescues visual cortical neurons from cyanide-induced apoptosis. Neurosci 139:639-649, 2006.
	Liang HL and MTT Wong-Riley: Activity-dependent regulation of nuclear respiratory factor-1, nuclear respiratory factor-2, and peroxisome proliferator-activated receptor gamma coactivator-1 in neurons. NeuroReport 17:401-405, 2006.
	Liang HL, S Ongwijitwat and MTT Wong-Riley: Bigenomic functional regulation of all 13 cytochrome c oxidase subunit transcripts in rat neurons in vitro and in vivo. Neurosci 140:177-190, 2006.
	Ongwijitwat S, HL Liang, EM Graboyes and MTT Wong-Riley: Nuclear respiratory factor 2 senses changing cellular energy demands and its silencing down-regulates cytochrome oxidase and other target gene mRNAs. Gene 374:39-49, 2006.
	Ongwijitwat S and MTT Wong-Riley: Is nuclear respiratory factor 2 a master transcriptional coordinator for all ten nuclear-encoded cytochrome c oxidase subunits in neurons? Gene 360:65-77, 2005.
	Wong-Riley MTT, HL Liang, JT Eells, MM Henry, E Buchmann, M Kane and HT Whelan: Photobiomodulation directly benefits primary neurons functionally inactivated by toxins: Role of cytochrome c oxidase. J Biol Chem 280:4761-4771, 2005.
	Wong-Riley MTT and Q Liu: Neurochemical development of brain stem nuclei involved in the control of respiration. Invited review. In Special Issue on "Development of Respiratory Control". R. Bavis and J. Carroll (eds.) Respiratory Physiology & Neurobiology 149:83-98, 2005.
	Ongwijitwat S and MTT Wong-Riley: Functional analysis of the rat cytochrome c oxidase subunit 6A1 promoter in primary neurons. Gene 337:163-171, 2004.
	Yang SJ, HL Liang, G Ning and MTT Wong-Riley: Ultrastructural study of depolarization-induced translocation of NRF-2 transcription factor in cultured rat visual cortical neurons. Eur J Neurosci 19:1153-1162, 2004.
	Zhang C and M Wong-Riley: Synthesis and degradation of cytochrome oxidase subunit mRNAs in neurons: Differential bigenomic regulation by neuronal activity. J Neurosci Res 60:338-344, 2000.
	Wong-Riley MTT: Primate Visual Cortex: Dynamic metabolic organization and plasticity revealed by cytochrome oxidase. In Cerebral Cortex, Vol. 10, Primary Visual Cortex in Primates. Peters A and K Rockland (eds.) New York, Plenum Press, pp. 141-200, 1994.
	Wong-Riley MTT: Cytochrome oxidase: an endogenous metabolic marker for neuronal activity. Trends in Neurosci 12:94-101, 1989.