Research Groups
Mouse Molecular Genetics
Research Interests and Description
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 (with or without the EDA domain) in different pathological conditions. We are using a mouse model developed in our lab, which is 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 and are currently studying the role of the FN isoforms in arterial thrombosis and in endothelial damage induced by diabetes. We are using this model to determine the molecular mechanisms associated with the modulation of splicing in pathological conditions. In addition, we have recently developed a mouse model of the Crigler-Najjar Syndrome and are addressing the mechanisms, and the possible therapeutic approaches, to cure the disease.
Our laboratory is also interested in the mechanisms regulating gene expression through the 3’ end of mRNAs. We are studying the mechanisms regulating tissue-specific alternative polyadenylation of the β-adducin gene. The β-adducin gene (ADD2) gene 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 acting on the distal brain polyadenylation site. We have found a number of potential protein factors participating in polyadenylation of ADD2, among them TDP-43, which binds to the downstream element of the brain-specific ADD2 polyadenylation site. We have also found “long distance enhancers” and “silencers” of polyadenylation. We are currently characterizing the trans-acting factors mediating these effects in β-adducin pre-mRNA 3’ end processing.
Recent Publications
Kohan, M., Muro, A.F., Bader, R., Berkman, N. 2011. The extra domain A of fibronectin is essential for allergen-induced airway fibrosis and hyperresponsiveness in mice. J Allergy Clin Immunol 127, 439-446 PubMed link
White, E.S., Muro, A.F. 2011. Fibronectin splice variants: understanding their multiple roles in health and disease using engineered mouse models. IUBMB Life 63, 538-546 PubMed link
Kohan, M., Muro, A.F., White, E.S., Berkman, N. 2010. EDA-containing cellular fibronectin induces fibroblast differentiation through binding to {alpha}4{beta}7 integrin receptor and MAPK/Erk 1/2-dependent signaling. FASEB J. PubMed link
Morgan, M., Iaconcig, A., Muro, A.F. 2010. CPEB2, CPEB3 and CPEB4 are coordinately regulated by miRNAs recognizing conserved binding sites in paralog positions of their 3'-UTRs. Nucleic Acids Res. PubMed link
Porro, F., Rosato-Siri, M., Leone, E., Costessi, L., Iaconcig, A., Tongiorgi, E., Muro, A.F. 2010. 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 9, 84-96 PubMed link
White, E.S., Sagana, R.L., Booth, A.J., Yan, M., Cornett, A.M., Bloomheart, C.A., Tsui, J.L., Wilke, C.A., Moore, B.B., Ritzenthaler, J.D., Roman, J., Muro, A.F. 2010. Control of fibroblast fibronectin expression and alternative splicing via the PI3K/Akt/mTOR pathway. Exp Cell Res 316, 2644-2653 PubMed link
