The Role of Cerl2 in the Establishment of Left-Right Asymmetries during Axis Formation and Heart Development

Abstract

The formation of the asymmetric left-right (LR) body axis is one of the fundamental aspects of vertebrate embryonic development, and one still raising passionate discussions among scientists. Although the conserved role of nodal is unquestionable in this process, several of the details around this signaling cascade are still unanswered. To further understand this mechanism, we have been studying Cerberus-like 2 (Cerl2), an inhibitor of Nodal, and its role in the generation of asymmetries in the early vertebrate embryo. The absence of Cerl2 results in a wide spectrum of malformations commonly known as heterotaxia, which comprises defects in either global organ position (e.g., situs inversus totalis), reversed orientation of at least one organ (e.g., situs ambiguus), and mirror images of usually asymmetric paired organs (e.g., left or right isomerisms of the lungs). Moreover, these laterality defects are frequently associated with congenital heart diseases (e.g., transposition of the great arteries, or atrioventricular septal defects). Here, reviewing the knowledge on the establishment of LR asymmetry in mouse embryos, the emerging conclusion is that as necessary as is the activation of the Nodal signaling cascade, the tight control that Cerl2-mediates on Nodal signaling is equally important, and that generates a further regionalized LR genetic program in the proper time and space.

Coexistence of situs inversus totalis and hepatocellular carcinoma: A series of nine cases and a literature review

“… 6 The absence of Cerberus-like 2 (Cerl2), an inhibitor of Nodal, and zinc fingers in cerebellum 3 (ZIC3) missense mutations, results in malformations commonly known as heterotaxy syndrome, including SIT, which is characterized by mirror images of usually asymmetric paired organs and reversed orientation of at least one organ. 7 , 8 An embryologic and genetic study conducted by Bartram et al. reported that SIT results from disruption of the process of normal left–right axis specification during embryogenesis.…”

Understanding laterality disorders and the left-right organizer: Insights from zebrafish

“…In lateral plate mesoderm, Nodal signaling can activate its own transcription as well as other targets that include Lefty proteins that act as feedback inhibitors of Nodal signaling (Meno et al, 1996;Nakamura et al, 2006) and the homeobox transcription factor Pitx2 that can regulate genes involved in asymmetric morphogenesis of the heart and gastrointestinal tract (Logan et al, 1998;Piedra et al, 1998;Ryan et al, 1998;Yoshioka et al, 1998;Shiratori et al, 2001;Kurpios et al, 2008) (Figure 2A). Cellular and molecular details of this conserved asymmetric Nodal signaling pathway have been described in recent review articles (Shiratori and Hamada 2014;Belo, Marques, and Inacio 2017;Zinski, Tajer, and Mullins 2018;Hamada, 2020). Importantly, genetic analyses in animal models and humans indicates that mutations that disrupt Nodal signaling can result in organ laterality disorders (Barnes and Black 2016;Montague, Gagnon, and Schier 2018;Li et al, 2019).…”

DAND5 Inactivation Enhances Cardiac Differentiation in Mouse Embryonic Stem Cells

“…Furthermore, some Cerberus/Dan family members, including DAND5, are multivalent antagonists that also bind to and inhibit BMP and Wnt ligands (Belo et al, 2009). Interestingly, we have reported that loss-of-function of DAND5 in mice leads to a massive increase of the ventricular heart wall's thickness caused by an increased mitotic index of the cardiomyocytes (CMs) at the compact myocardium (Araújo et al, 2014;Belo et al, 2017). Allied to these, increased levels of phosphorylated-SMAD2 and increased Ccnd1 expression levels were detected in the hearts of Dand5 knockout (Dand5 KO) neonatal mice (Araújo et al, 2014).…”