Department of Biochemistry
School of Medicine & Biomedical Sciences
Faculty
MICHAEL D. GARRICK, Ph.D.
Professor
Molecular Basis of Erythroid Differentiation
Our research has four long-term themes: 1) The molecular basis of differential gene expression among tissues and during development. 2) Iron metabolism in erythroid cells, the GI tract, neurons and other tissues. 3) Application of molecular and genetic advances to inherited diseases. 4) Gene variation in populations and divergence of gene loci during evolution.
Current research involves multiple rodent models: We recently showed that a G185R mutation in DMT1/DCT1/Nramp2, an iron transporter, is the mutation in the Belgrade rat. This means that this rat has lost the function of the main iron transporter in the GI tract and the transporter responsible for most iron flux within cells. DMT1 is also responsible for uptake and flux of 7 other metals such as Mn, Co and Ni. Yet the rat survives! The microcytic mouse has an identical mutation. The hemoglobin deficit mouse has a mutation in a different gene that also affects iron metabolism. We are now trying to learn which metals are affected by the mutation in the Belgrade rat. We are also trying to evaluate the roles of 4 forms of DMT1 that should have different modes of regulation by iron. Our data provide convincing evidence that the 4 forms are distributed differently within cells in a tissue specific fashion.
Fig. 1. Uptake and utilization of iron by the reticulocyte. The physiological pathway involves binding and internalization of transferrin, release of Fe from transferrin within the endosome due to acidification, and recycling of the apo-transferrin on its receptor to the cell surface.
Selected Recent Publications
Garrick, M.D. and Garrick, L.M. Cellular iron transport. (2009) Biochim. Biophysi. Acta 1790:309-325.
Salazar, J., Mena, N., Hunot, S., Prigent, A., Alvarez-Fischer, D., Arredondo, M., Duyckaerts, C., Sazdovitch, V., Zhao, L., Garrick, L.M., Nuñez, M.T., Garrick, M.D., Raisman-Vozari, R. and Hirsch, E.C. (2008) Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson's disease. Proc. Natl. Acad. Sci. USA 105:18578-18583.
Collins, J.F., Hu, Z., Ranganathan, P.N., Feng, D., Garrick, L.M, Garrick, M.D., & Browne, R.W. (2008) Induction of arachidonate 12-lipoxygenase (Alox15) in intestine of iron-deficient rats correlates with the production of biologically active lipid mediators. Amer. J. Physiol. GI and Liver Physiol. 294:948-962 doi:10.1152/ajpgi.00274.2007.
Koeppen, A.H., Michael, S., Knutson, M.D., Qian, J., Petrocine, S.V., Levi, S., Santambrogio, P., Garrick, M.D., & Lamarche, J.B. (2007) The dentate nucleus in Friedreich’s ataxia: The role of iron-responsive proteins. Acta Neuropathol. (Berlin), 114:163-173.Garrick, M.D. and Garrick, L.M. (2007) Loss of rapid transferrin receptor recycling due to a mutation in Sec15l1 in hbd mice. Biochim. Biophysi. Acta – Molec. Cell Res. 1773:105–108.
Ghio, A.J., Turi, J.L., Madden, M.C., Dailey, L.A., Richards, J.D., Stonebuerner, J.G., Morgan, D.L., Singleton, S., Garrick, L.M., Garrick, M.D. (2007) Lung injury after ozone exposure is iron dependent. Am J Physiol Lung Cell Mol Physiol 292: L134-L143.
Garrick, M. D., Kuo, H.C., Vargas, F., Singleton, S., Zhao, L., Smith, J. J., Paradkar, P., Roth, J., Garrick. L. (2006) Comparison of mammalian cell lines expressing distinct isoforms of divalent metal transporter 1 in a tetracyclin-regulated fashion. Biochem. J. (2006) 398, 539-546 (Printed in Great Britian) doi: 10.1042/BJ20051987
Michael, S., Petrocine, S. V., Qian, J., Lamarche, J. B., Knutson, M. D., Garrick, M. D., and Koeppen, A. H. (2006) Iron and iron-responsive proteins in the cardiomyopathy of Friedreich's ataxia. The Cerebellum 5:257-267.
Garrick, M.D., and Garrick, L.M. (2004) Divalent metal transporter DMT1 (SLC11A2) Chapter 3.2 in Membrane Transporter Diseases, pp. 107-122 (ed. by S. Broer and C. Wagner), Kluwer, Dordrecht.Kuo, H.C., Smith, J.J., Lis, A., Zhao, L., Gonsiorek, E.A., Zhou, X., Higgins, D.M., Roth, J.A., Garrick, M. D. & Garrick, L. (2004) A computer-identified nuclear localization signal in exon 1A of the transporter DMT1 is essentially ineffective in nuclear targeting. J. Neurosci. Res. 76:497-511.
Turi, J.L., Yang, F., Garrick, M.D., Piantadosi, C.A. & Ghio, A.J. (2004) The iron cycle and oxidative stress in the lung. Free Rad. Biol. Med. 36:850-857.
Garrick, M.D., Núñez, M.T., Olivares, M., and Harris, E.D. (2003) Parallels and Contrasts between Iron and Copper Metabolism. BioMetals 16: 1-8.
Garrick, M.D., Dolan, K.G., Horbinski, C., Ghio, A., Higgins, D., Porubcin, M., Moore, E.G., Hainsworth, L.N., Umbreit, J.N., Conrad, M.E., Feng, L., Lis, A., Roth, J.A., Singleton, S., and Garrick, L.M. (2003) DMT1: A Mammalian Transporter for Multiple Metals. BioMetals 16: 41-54.
Ghio, A.J., Wang, X., Silbajoris, R., Garrick, M.D., Piantadosi, C.A., and Yang, F. DMT1 expression is increased in the lungs of hypotransferrinemic mice. Amer. J. Physiol. Lung Cell. Mol. Physiol. In press.
Garrick, M.D. & Dolan, K.G. (2002) An Expression System for a Transporter of Iron and Other Metals. Chapter 18 in Ultrastructure and Molecular Biology Protocols for Oxidants and Antioxidant, Methods in Molecular Biology, vol. 196, pp. 147-154 (ed. by D. Armstrong), Humana, Totawa.*|
Roth, J.A., Horbinski, C., Higgins, D., Lein, P., and Garrick, M.D. (2002) Mechanism of Manganese-induced Rat Pheochromocytoma (PC12) Cell Death and Cell Differentiation. NeuroToxicology 23: 147-157|.
Roth, J.A., Feng, L., Dolan, K.G., Lis, A., and Garrick, M.D. (2002) Effect of the Iron Chelator, Desferrioximine, on Manganese-Induced Toxicity of Rat Pheochromocytoma (PC12) Cells. J. Neurosci. Res. 68: 76-83.
Wang, X., Ghio, A.J., Yang, F., Dolan, K.G., Garrick, M.D., and Piantadosi, C.A. (2002) Iron Uptake and Nramp2/DMT1/DCT1 in Human Bronchial Epithelial Cells. Amer. J. Physiol. Lung Cell. Mol. Physiol. 282: L987-995.
Zywicke, H.A., van Gelderen, P., Connor, J.R., Burdo, J.R., Garrick, M.D., Dolan, K.G., Frank, J.A., and Bulte, J.W.M. (2002) Microscopic R2* mapping of reduced brain iron in the Belgrade rat. Ann. Neurol. 52: 102-105.
Burdo, J.R., Menzies, S.L., Simpson, I.A., Garrick, L.M., Garrick, M.D., Dolan, K.G., Haile, D.J., Beard, J.L., and Connor, J.R. (2001) Distribution of Divalent Metal Transporter 1 and Metal Transport Protein 1 in the Normal and Belgrade rat. J. Neurosci. Res. 66: 1198-1207.
Conrad, M.E., Umbreit, J.N., Moore, E.G., Hainsworth, L.N., Latour, L.F., Feagin, J.E., Nakada, M.T., Dolan, K.G. and Garrick, M.D. (2000) Separate Pathways for Cellular Uptake of Ferric and Ferrous Iron. Amer. J. Physiol. Gastrointest. Liver Physiol. 279: G767-G774.