Dr. Michaud's research interests are in using the tools of mouse genetics and genomics to examine the interactions between genetic pathways and environmental factors in the determination of human health and disease, with an emphasis on skin biology. A new project in the lab focuses on the systems biology of the mammalian primary cilium.

Human health is characterized by the well-orchestrated interactions among thousands of genes and a myriad of environmental variables. The ultimate goal in the study of complex biological systems is to understand the molecular mechanisms underlying the intricate interactions among genetically controlled biochemical pathways, the effects of environmental exposures, and the impact of aging. The Human Genome Project has laid the foundation for this level of understanding of biology by determining the DNA sequence of the estimated 25,000 genes that comprise the human genome. The next major challenge will be to use this DNA-sequence information to determine the role that each gene plays in human health, disease, and in interactions with environmental exposures.

The high degree of similarity between the DNA sequences of human and mouse genes, the similar biology of these two mammals, and the ease with which the mouse genome can be experimentally manipulated, make the mouse an ideal model organism for interpreting human gene function. By inducing mutations in mouse genes and by capitalizing on the genetic variation present in diverse strains of inbred mice, we gain insight into the functions, regulatory networks, and gene-environment interactions of the homologous human genes.

The Michaud lab has two broad goals. The first goal is to develop new strategies and resources to facilitate high-throughput, cost-effective, gene-driven mutagenesis and analysis of mouse gene function (see Michaud et al., 2005, BMC Genomics 6:164). These strategies include gene-driven ENU-mutagenesis screens in mice, conditional gene targeting in mouse ES cells, and transgenics for generating new mouse mutations, and cDNA microarrays for determining the genetic pathways in which single-gene mutations function. The second goal is to apply this genetics and functional genomics approach to a systems-biology based understanding of the development and physiology of the skin.

The skin is a highly metabolic organ with the largest surface area in the body, and is composed of multiple tissue layers, each performing a specific role. As the primary border of the body and the first organ to come into contact with the external environment, the skin has important protective and defensive functions, especially with regard to potentially toxic chemical and biological environmental exposures. The outermost layer of the skin, the epidermis, is composed of one main cell type, the keratinocyte, which undergoes a precisely defined program of proliferation, differentiation, and programmed cell death to produce a continually renewable barrier for the body. Numerous genetic pathways and external environmental factors affect the delicate balance between cell growth, differentiation, and death, although most of the genetic networks regulating these biological processes remain to be elucidated. Genetic defects in multigenic biological processes may lead to innumerable skin diseases, including cancer, and may affect the degree of susceptibility of different individuals to the harmful effects of radiological, chemical and biological environmental exposures. Thus, the skin is an ideal organ system for developing a biological pathway-based approach to functional genomics, and for studying such complex processes as pigmentation, stem cell biology, cellular growth, differentiation, apoptosis, DNA repair, and cancer.

A new project in Dr. Michaud's lab involves the systems biology of the primary cilium. See Michaud, E. J., and B. K. Yoder. 2006. The primary cilium in cell signaling and cancer. Cancer Res. 66:6463-6467. (Invited review)

Systems Biology of the Mammalian Cilium: A Cellular Organelle Essential for Human Health and Development

The primary cilium is a small, immotile, antenna-like structure that emanates from the surface of virtually every cell in the mammalian body and functions as a sensory organelle. Recent studies revealed that the primary cilium receives both mechanical and biochemical signals from other cells and the environment, and transmits these signals to the nucleus to elicit a cellular response. The proteins necessary for assembling the cilium, for transporting receptors and channels to the cilium membrane, and for conveying sensory information from the cilium back to the cell body are moved bi-directionally within the cilium in a process called intraflagellar transport (IFT). Mutations in primary cilia genes cause a variety of different human genetic diseases, in part because primary cilia are required for the normal function of the sonic hedgehog (Shh), Wingless-Int (Wnt), and Platelet-derived growth factor receptor alpha (Pdgfra) signaling pathways, which are important for the development and homeostasis of many organ systems, including the skin and hair follicle. Comparative genomics and proteomics studies have revealed that the cilia proteome has been highly conserved throughout the evolution of eukaryotes and consists of approximately 300-500 proteins. However, the biological functions of the majority of these proteins remain to be discovered. We are initiating a systems-biological approach to understanding cilia assembly and function. For putative cilia genes that have not yet been localized to cilia in model organisms, we are performing translational GFP assays in transgenic worms (C. elegans). For cilia genes that have already been localized to cilia in model organisms, we are generating mutations in orthologous mouse cilia genes utilizing gene-driven ENU-induced mutagenesis, conditional gene targeting, and gene traps.

• Michaud, E. J., and B. K. Yoder. 2006. The primary cilium in cell signaling and cancer. Cancer Res. 66:6463-6467. (Invited review)
• Michaud, E. J., C. T. Culiat, M. L. Klebig, P. E. Barker, K. T. Cain, D. J. Carpenter, L. L. Easter, C. M. Foster, A. W. Gardner, Z. Y. Guo, K. J. Houser, L. A. Hughes, M. K. Kerley, Z. Liu, R. E. Olszewski, I. Pinn, G. D. Shaw, S. G. Shinpock, A. M. Wymore, E. M. Rinchik, and D. K. Johnson. 2005. Efficient gene-driven germ-line point mutagenesis of C57BL/6J mice. BMC Genomics 6:164.
• Haycraft C. J., B. Banizs, Y. Aydin-Son, E. J. Michaud, and B. K. Yoder. 2005. Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet. 1:e53.
• Johnson, D. K., E. M. Rinchik, N. Moustaid-Moussa, D. R. Miller, R. W. Williams, E. J. Michaud, M. M. Jablonski, A. Elberger, K. Hamre, R. Smeyne, E. Chesler, and D. Goldowitz. 2005. Phenotype screening for genetically determined age-onset disorders and increased longevity in ENU-mutagenized mice. AGE 27:75-90.
• Vo-Dinh, T., D. L. Stokes, M. B. Wabuyele, M. E. Martin, J. M. Song, R. Jagannathan, E. Michaud, R. J. Lee, and X. Pan. 2004. A hyperspectral imaging system for in vivo optical diagnostics. Hyperspectral imaging basic principles, instrumental systems, and applications of biomedical interest. IEEE Eng. Med. Biol. Mag. 23:40-49. (Invited paper)
• Kuklin, A. I., R. L. Mynatt, M. L. Klebig, L. L. Kiefer, W. O. Wilkison, R. P. Woychik, and E. J. Michaud. 2004. Liver-specific expression of the agouti gene in transgenic mice promotes liver carcinogenesis in the absence of obesity and diabetes. Mol. Cancer 3:17.
• Wu, M., E. J. Michaud, and D. K. Johnson. 2003. Cloning, functional study and comparative mapping of Luzp2 to mouse Chromosome 7 and human Chromosome 11p13-11p14. Mamm. Genome 14:323-334.
• Zhang, Q., N. S. Murcia, L. R. Chittenden, W. G. Richards, E. J. Michaud, R. P. Woychik, and B. K. Yoder. 2003. Loss of the Tg737 protein results in skeletal patterning defects. Dev. Dyn. 227:78-90.
• Miltenberger, R. J., K. Wakamatsu, S. Ito, R. P. Woychik, L. B. Russell, and E. J. Michaud. 2002. Molecular and phenotypic analysis of 25 recessive, homozygous-viable, alleles at the mouse agouti locus. Genetics 160:659-674.

• Johnson, D. K., D. A. Carpenter, C. T. Culiat, K. A. Goss, M. L. Klebig, E. J. Michaud, D. R. Miller, L. B. Russell, Y. You, and E. M. Rinchik. 2000. A phenotype-driven approach to the molecular and functional analysis of the mouse genome. In: Microbial Status and Genetic Evaluation of Mice and Rats, Proceedings of the 1999 US/Japan meeting, National Research Council, Washington DC, pp. 105-115.
• Paulus, M. J., S. S. Gleason, H. Sari-Sarraf, D. K. Johnson, C. J. Foltz, D. W. Austin, M. E. Easterly, E. J. Michaud, M. S. Dhar, P. R. Hunsicker, J. W. Wall, M. Schell. 2000. High-resolution X-ray CT screening of mutant mouse models. Proc. SPIE 3921:270-279
• Khrebtukova, I., A. Kuklin, R. P. Woychik, and E. J. Michaud. 1999. Alternative processing of the human and mouse Raly genes. Biochim. Biophys. Acta 1447:107-112.
• Miltenberger, R. J., R. L. Mynatt, B. D. Bruce, W. O. Wilkison, R. P. Woychik, and E. J. Michaud. 1999. An agouti mutation lacking the central basic domain induces yellow pigmentation but not obesity in transgenic mice. Proc. Natl. Acad. Sci. USA 96:8579-8584.
• Khrebtukova, I., E. J. Michaud, C. M. Foster, K. L. Stark, D. J. Garfinkel, and R. P. Woychik. 1999. Corrigendum to: 'Utilization of microhomologous recombination in yeast to generate targeting constructs for mammalian genes' [Mutation res. 401 (1998) 11-25]. Mutat. Res. 423:191.
• Khrebtukova, I., E. J. Michaud, C. M. Foster, K. L. Stark, D. J. Garfinkel, and R. P. Woychik. 1998. Utilization of microhomologous recombination in yeast to generate targeting constructs for mammalian genes. Mutat. Res. 401:11-25.
• Michaud, E. J., R. L. Mynatt, R. J. Miltenberger, M. L. Klebig, J. E. Wilkinson, M. B. Zemel, W. O. Wilkison, and R. P. Woychik. 1997. Role of the agouti gene in obesity. J.Endocrinol. 155:207-209.
• Yoder, B. K., W. G. Richards, C. Sommardahl, W. E. Sweeney, E. J. Michaud, J. E. Wilkinson, E. D. Avner, and R. P. Woychik. 1997. Differential rescue of the renal and hepatic disease in an autosomal recessive polycystic kidney disease mouse mutant: a new model to study the liver lesion. Am. J. Pathol. 150:2231-2241.
• Yoder, B. K., W. G. Richards, C. Sommardahl, W. E. Sweeney, E. J. Michaud, J. E. Wilkinson, E. D. Avner, and R. P. Woychik. 1996. Functional correction of the renal defects in a mouse model for ARPKD through expression of the cloned wild-type Tg737 cDNA. Kidney Int. 50:1240-1248.
• Jones, B. H., J. H. Kim, M. B. Zemel, R. P. Woychik, E. J. Michaud, W. O. Wilkison, and N. Moustaïd. 1996. Upregulation of adipocyte metabolism by agouti protein: possible paracrine actions in yellow mouse obesity. Am. J. Physiol. 270:E192-E196.
• Zemel, M. B., J. H. Kim, R. P. Woychik, E. J. Michaud, S. H. Kadwell, I. R. Patel, and W. O. Wilkison. 1995. Agouti regulation of intracellular calcium: role in the insulin resistance of viable yellow mice. Proc. Natl. Acad. Sci. USA 92:4733-4737.
• Michaud, E. J., and A. C. Echternacht. 1995. Geographic variation in the life history of the lizard Anolis carolinensis and support for the pelvic constraint model. J. Herpetol. 29:86-97.
• Echternacht, A. C., M. A. Wilson, E. J. Michaud, and D. M. MacDonald. 1995. Anolis sagrei. Herp. Review. 26:107.
• Michaud, E. J., M. J. van Vugt, S. J. Bultman, H. O. Sweet, M. T. Davisson, and R. P. Woychik. 1994. Differential expression of a new dominant agouti allele (A^iapy) is correlated with methylation state and is influenced by parental lineage. Genes Dev. 8:1463-1472.
• Michaud, E. J., S. J. Bultman, M. L. Klebig, M. J. van Vugt, L. J. Stubbs, L. B. Russell, and R. P. Woychik. 1994. A molecular model for the genetic and phenotypic characteristics of the mouse lethal yellow (A^y) mutation. Proc. Natl. Acad. Sci. USA 91:2562-2566.
• Bultman, S. J., M. L. Klebig, E. J. Michaud, H. O. Sweet, M. T. Davisson, and R. P. Woychik. 1994. Molecular analysis of reverse mutations from nonagouti (a) to black-and-tan (a^t) and white-bellied agouti (A^w) reveals alternative forms of agouti transcripts. Genes Dev. 8:481-490.
• Michaud, E. J., S. J. Bultman, L. J. Stubbs, and R. P. Woychik. 1993. The embryonic lethality of homozygous lethal yellow mice (A^y/A^y) is associated with the disruption of a novel RNA-binding protein. Genes Dev. 7:1203-1213.
• Bultman, S. J., E. J. Michaud, and R. P. Woychik. 1992. Molecular characterization of the mouse agouti locus. Cell 71:1195-1204.
• Dixon, J. R., and E. J. Michaud. 1992. Shaw's black-backed snake (Liophis melanotus) (Serpentes: Colubridae) of Northern South America. J. Herpetol. 26:250-259.
• Michaud, E. J. 1991. The evolution of size in a temperate zone Anolis (Sauria: Iguanidae). In: The Fourth Anolis Newsletter (eds. J. B. Losos and G. C. Mayer), pp. 104-112. Smithsonian Inst. Press, Washington, D.C.
• Michaud, E. J., and J. R. Dixon. 1989. Prey items of 20 species of the neotropical colubrid snake genus Liophis. Herp. Review 20:39-41.
• Michaud, E. J., and J. R. Dixon. 1987. Taxonomic revision of the Liophis lineatus complex (Reptilia: Colubridae) of Central and South America. Milwaukee Publ. Mus., Contr. Biol. & Geol. 71:1-26.