Rosenthal GroupPublications
Antioxidant amelioration of dilated cardiomyopathy caused by conditional deletion of NEMO/IKKgamma in cardiomyocytes.
Kratsios, P., Huth, M., Temmerman, L., Salimova, E., Al Banchaabouchi, M., Sgoifo, A., Manghi, M., Suzuki, K., Rosenthal, N. & Mourkioti, F.
Circ Res. 2010 Jan 8;106(1):133-44. Epub 2009 Oct 22.
RATIONALE: Insight into the function of nuclear factor (NF)-kappaB in the adult heart has been hampered by the embryonic lethality of constitutive NF-kappaB inactivation. OBJECTIVE: The goal of the present study was therefore to gain insights into the role of NF-kappaB pathway specifically in mouse cardiomyocytes by conditional deletion of the NF-kappaB essential modulator (NEMO). METHODS AND RESULTS: Using a Cre/loxP system, we disrupted the Nemo gene in a cardiomyocyte-specific manner in the heart, which simulated gene expression changes underlying human heart failure and caused adult-onset dilated cardiomyopathy accompanied by inflammation and apoptosis. Pressure overload challenges of NEMO-deficient young hearts precociously induced the functional decrements that develop spontaneously in older knockout animals. Moreover, oxidative stress in NEMO-deficient cardiomyocytes is a critical pathological component that can be attenuated with antioxidant diet in vivo. CONCLUSIONS: These results reveal an essential physiological role for NEMO-mediated signaling in the adult heart to maintain cardiac function in response to age-related or mechanical challenges, in part through modulation of oxidative stress.
Redeployment of Notch1 embryonic signaling mediates cardiac morphogenesis and promotes myocardial repair in the adult.
Kratsios, P., Catela, C., Salimova, E., Huth, M., Berno, V., Rosenthal, N. Mourkioti, F.
Circ. Research, in press
A CREB-C/EBPbeta cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair.
Ruffell, D., Mourkioti, F., Gambardella, A., Kirstetter, P., Lopez, R.G., Rosenthal, N. & Nerlov, C.
Proc Natl Acad Sci U S A. 2009 Oct 13;106(41):17475-80. Epub 2009 Sep 24.
Macrophages play an essential role in the resolution of tissue damage through removal of necrotic cells, thus paving the way for tissue regeneration. Macrophages also directly support the formation of new tissue to replace the injury, through their acquisition of an anti-inflammatory, or M2, phenotype, characterized by a gene expression program that includes IL-10, the IL-13 receptor, and arginase 1. We report that deletion of two CREB-binding sites from the Cebpb promoter abrogates Cebpb induction upon macrophage activation. This blocks the downstream induction of M2-specific Msr1, Il10, II13ra, and Arg-1 genes, whereas the inflammatory (M1) genes Il1, Il6, Tnfa, and Il12 are not affected. Mice carrying the mutated Cebpb promoter (betaDeltaCre) remove necrotic tissue from injured muscle, but exhibit severe defects in muscle fiber regeneration. Conditional deletion of the Cebpb gene in muscle cells does not affect regeneration, showing that the C/EBPbeta cascade leading to muscle repair is muscle-extrinsic. While betaDeltaCre macrophages efficiently infiltrate injured muscle they fail to upregulate Cebpb, leading to decreased Arg-1 expression. CREB-mediated induction of Cebpb expression is therefore required in infiltrating macrophages for upregulation of M2-specific genes and muscle regeneration, providing a direct genetic link between these two processes.
Multiple congenital malformations of Wolf-Hirschhorn syndrome are recapitulated in Fgfrl1 null mice.
Catela, C., Bilbao-Cortes, D., Slonimsky, E., Kratsios, P., Rosenthal, N. & te Welscher, P.
Dis Model Mech. 2009 May-Jun;2(5-6):283-94. Epub 2009 Apr 21.
Wolf-Hirschhorn syndrome (WHS) is caused by deletions in the short arm of chromosome 4 (4p) and occurs in about one per 20,000 births. Patients with WHS display a set of highly variable characteristics including craniofacial dysgenesis, mental retardation, speech problems, congenital heart defects, short stature and a variety of skeletal anomalies. Analysis of patients with 4p deletions has identified two WHS critical regions (WHSCRs); however, deletions targeting mouse WHSCRs do not recapitulate the classical WHS defects, and the genes contributing to WHS have not been conclusively established. Recently, the human FGFRL1 gene, encoding a putative fibroblast growth factor (FGF) decoy receptor, has been implicated in the craniofacial phenotype of a WHS patient. Here, we report that targeted deletion of the mouse Fgfrl1 gene recapitulates a broad array of WHS phenotypes, including abnormal craniofacial development, axial and appendicular skeletal anomalies, and congenital heart defects. Fgfrl1 null mutants also display a transient foetal anaemia and a fully penetrant diaphragm defect, causing prenatal and perinatal lethality. Together, these data support a wider role for Fgfrl1 in development, implicate FGFRL1 insufficiency in WHS, and provide a novel animal model to dissect the complex aetiology of this human disease.