title: Targeted inactivation of Cerberus like-2 leads to left ventricular cardiac hyperplasia and systolic dysfunction in the mouse.
abstract: Previous analysis of the Cerberus like 2 knockout (Cerl2-/-) mouse revealed a significant mortality during the first day after birth, mostly due to cardiac defects apparently associated with randomization of the left-right axis. We have however, identified Cerl2-associated cardiac defects, particularly a large increase in the left ventricular myocardial wall in neonates that cannot be explained by laterality abnormalities. Therefore, in order to access the endogenous role of Cerl2 in cardiogenesis, we analyzed the embryonic and neonatal hearts of Cerl2 null mutants that did not display a laterality phenotype. Neonatal mutants obtained from the compound mouse line Cer2-/-::Mlc1v-nLacZ24+, in which the pulmonary ventricle is genetically marked, revealed a massive enlargement of the ventricular myocardium in animals without laterality defects. Echocardiography analysis in Cerl2-/- neonates showed a left ventricular systolic dysfunction that is incompatible with a long lifespan. We uncovered that the increased ventricular muscle observed in Cerl2-/- mice is caused by a high cardiomyocyte mitotic index in the compact myocardium which is mainly associated with increased Ccnd1 expression levels in the left ventricle at embryonic day (E) 13. Interestingly, at this stage we found augmented left ventricular expression of Cerl2 levels when compared with the right ventricle, which may elucidate the regionalized contribution of Cerl2 to the left ventricular muscle formation. Importantly, we observed an increase of phosphorylated Smad2 (pSmad2) levels in embryonic (E13) and neonatal hearts indicating a prolonged TGFβs/Nodal-signaling activation. Concomitantly, we detected an increase of Baf60c levels, but only in Cerl2-/- embryonic hearts. These results indicate that independently of its well-known role in left-right axis establishment Cerl2 plays an important role during heart development in the mouse, mediating Baf60c levels by exerting an important control of the TGFβs/Nodal-signaling pathway.
authors.affiliation: Laboratory of Embryology and Genetic Manipulation, Regenerative Medicine Program, Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, Campus de Gambelas, Faro, Portugal; IBB - Institute for Biotechnology and Bioengineering, Centro de Biomedicina Molecular e Estrutural, Universidade do Algarve, Campus de Gambelas, Faro, Portugal; PhD Program in Biomedical Sciences, Universidade do Algarve, Campus de Gambelas, Faro, Portugal.
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: Araújo
authors.affiliation: Laboratory of Embryology and Genetic Manipulation, Regenerative Medicine Program, Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, Campus de Gambelas, Faro, Portugal; IBB - Institute for Biotechnology and Bioengineering, Centro de Biomedicina Molecular e Estrutural, Universidade do Algarve, Campus de Gambelas, Faro, Portugal.
authors.forename: Sara
authors.initials: S
authors.lastname: Marques
authors.affiliation: Laboratory of Embryology and Genetic Manipulation, Regenerative Medicine Program, Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, Campus de Gambelas, Faro, Portugal; IBB - Institute for Biotechnology and Bioengineering, Centro de Biomedicina Molecular e Estrutural, Universidade do Algarve, Campus de Gambelas, Faro, Portugal; CEDOC - Chronic Diseases Research Center, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.
authors.forename: José António
authors.initials: JA
authors.lastname: Belo
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism; D009202:Cardiomyopathies / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D006965:Hyperplasia / Q000378:metabolism* / Q000473:pathology*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism; D055457:Nodal Protein / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000378:metabolism* / Q000473:pathology*
chemical_list: C119003:Dte protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D055457:Nodal Protein; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D019938:Cyclin D1