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.
Highlights
The heart is the first organ to be formed to allow the efficient supply of the increasing nutritional requirements of the growing embryo [1]
It has been extensively reported that laterality defects are characterized by failure in the left–right axis (L/R) axis establishment followed by randomized positioning of the asymmetrical visceral organs [23]
In order to identify the animals without laterality defects (LD), we started our analysis by performing echocardiographic examination of Cerl22/ 2 neonatal hearts, and complemented it with observation of the relative positions of the heart and arteries, lung lobulation, liver and stomach disposition within the body
Summary
The heart is the first organ to be formed to allow the efficient supply of the increasing nutritional requirements of the growing embryo [1]. The heart starts to be formed at gastrulation with the formation of the cardiac crescent at the anterior side of the embryo [5], which contributes to the heart primordium or first heart field (FHF) [6]. Cells from FHF will mainly give rise to the left ventricle (LV) [1]. Later, another region can be identified, the secondary heart field (SHF) that will mainly contribute to the right ventricle (RV) and outflow tract (OFT) [7]. The heart primordium region fuses at the embryonic midline to form a primitive heart tube [8]
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