Research Groups

Mouse Molecular Genetics

Research Interests and Description

Group Members

Research Interests

Transgenic and KO models of genes related to human diseases. Regulation of gene expression through the 3' ends of the mRNAs.

Description of Research

The research interests of the Mouse Molecular Genetics Group focus on the study of the functions of genes and proteins related to human diseases, using mouse models. The laboratory is currently addressing the role of FN isoforms (both containing and without the EDA domain) in different pathological conditions. We are using a mouse model developed in the lab, devoid of regulated splicing in the EDA exon, thus committing the FN pre-mRNA to undergo either constitutive inclusion or constitutive exclusion of the exon. We have found that mice devoid of the EDA exon are unable to develop pulmonary fibrosis. After the fibrotic stimulus those mice have reduced differentiation of fibroblast into myofibroblasts, probably due to the inability of that strain to activate latent TGF-b. We are currently studying the role of the FN isoforms in arterial thrombosis and in endothelial damage induced by diabetes.

Another interest is the mechanisms that regulate gene expression through the 3’ ends of the mRNAs. Two models are currently being studied: tissue-specific alternative polyadenylation of the β-adducin gene and gene expression regulation of CPEB2, mediated by miRNAs that recognize its 3’ UTR.

The β-adducin gene (ADD2) utilizes tissue specific promoters associated to tissue specific polyadenylation sites: one promoter is used in erythroid tissues while the other, located 50 kbp upstream, is used in brain. Interestingly, one proximal polyadenylation region is used in erythroid tissues generating a 3’ UTR of about 1-1.5 kb, while a distal one is used in brain to form a 3’ UTR of 6-7 kb, depending on the species. We have identified the main cis-acting sequences on the distal brain polyadenylation site and we are currently characterizing the trans-acting factors that regulate polyadenylation of the β-adducin transcript in a tissue-specific manner.

CPEB is a family of cytoplasmic proteins that bind sequences in the 3’UTR of mRNAs and regulate their polyadenylation status and, consequently, their translation efficiency. The 3’UTR of the members of the CPEB2 subfamily of genes (CPEB2, 3 and 4) is extremely conserved in evolution suggesting that important selection pressure acted to maintain the function of this region. One important function of the 3’UTR is the regulation of mRNA fate through miRNAs. We have demonstrated that some miRNA target sites are conserved and are functional in all members of the CPEB2 subfamily, and many of these miRNAs are known to be involved in disease. We are exploring the possibility of a common regulatory mechanism for the subfamily transcripts mediated by miRNAs.

Recent Publications

Porro, F., Rosato-Siri, M., Leone, E., Costessi, L., Iaconcig, A., Tongiorgi, E. and Muro, A.F. 2009. beta-adducin (Add2) KO mice show synaptic plasticity, motor-coordination and behavioral deficits accompanied by changes in the expression and phosphorylation levels of the alpha- and gamma-adducin subunits. Genes, Brain Behav. In press

Bazigou, E., Xie, S., Chen, C., Weston, A., Miura, N., Sorokin, L., Adams, R., Muro, A.F., Sheppard, D., Makinen, T. 2009. Integrin alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis. Dev. Cell. 17, 175-186

White, E.S., Baralle, F.E., Muro, A.F. 2008. New insights into form and function of fibronectin splice variants. J Pathol 216, 1-14

Muro, A.F., Moretti, F.A., Moore, B.B., Yan, M., Atrasz, R.G., Wilke, C.A., Flaherty, K.R., Martinez, F.J., Tsui, J.L., Sheppard, D., Baralle, F.E., Toews, G.B., White, E.S. 2008. An essential role for fibronectin extra type III domain A in pulmonary fibrosis. Am J Respir Crit Care Med. 177, 638-645

Babaev, V.R., Porro, F., Linton, M.F., Fazio, S., Baralle, F.E., Muro, A.F. 2008. Absence of regulated splicing of fibronectin EDA exon reduces atherosclerosis in mice. Atherosclerosis 197, 534-540

Chauhan, A.K., Kisucka, J., Cozzi, M.R., Walsh, M.T., Moretti, F.A., Battiston, M., Mazzucato, M., De Marco, L., Baralle, F.E., Wagner, D.D., Muro, A.F. 2008. Prothrombotic Effects of Fibronectin Isoforms Containing the EDA Domain. Arterioscler Thromb Vasc Biol 28, 296–301

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