The CapZ interacting protein Rcsd1 is required for cardiogenesis downstream of Wnt11a in Xenopus laevis

Abstract

Wnt proteins are critical for embryonic cardiogenesis and cardiomyogenesis by regulating different intracellular signalling pathways. Whereas canonical Wnt/β-catenin signalling is required for mesoderm induction and proliferation of cardiac progenitor cells, β-catenin independent, non-canonical Wnt signalling regulates cardiac specification and terminal differentiation. Although the diverse cardiac malformations associated with the loss of non-canonical Wnt11 in mice such as outflow tract (OFT) defects, reduced ventricular trabeculation, myofibrillar disorganization and reduced cardiac marker gene expression are well described, the underlying molecular mechanisms are still not completely understood. Here we aimed to further characterize Wnt11 mediated signal transduction during vertebrate cardiogenesis. Using Xenopus as a model system, we show by loss of function and corresponding rescue experiments that the non-canonical Wnt signalling mediator Rcsd1 is required downstream of Wnt11 for ventricular trabeculation, terminal differentiation of cardiomyocytes and cardiac morphogenesis. We here place Rcsd1 downstream of Wnt11 during cardiac development thereby providing a novel mechanism for how non-canonical Wnt signalling regulates vertebrate cardiogenesis.

The Wnt inhibitor Dkk1 is required for maintaining the normal cardiac differentiation program in Xenopus laevis

“…To further investigate the Dkk1 morphant heart morphology in more detail, we performed 3D imaging of affected embryos using optical projection tomography (OPT) and measured the heart size at stage 45 as described previously in another context (Hempel et al., 2017). We observed a significant decrease in atrial (a) and ventricular (v) width as well as in a-v length (Fig.…”

“…Note that there are two Wnt11 members in Xenopus that are expressed at different time points of development. Whereas wnt11b (formerly called XWnt11) is expressed early in development and is essential for specification of CPCs (Afouda et al., 2008; Pandur et al., 2002), Wnt11a (formerly called Wnt11R) functions during terminal differentiation (Garriock et al., 2005; Gessert et al., 2008; Hempel et al., 2017). Moreover, the loss-of-function effects of Dkk1 can at least in part be rescued by addition of wnt11a, indicating that some of the effects observed are indeed due to mis-regulated non-canonical Wnt signaling.…”

“…In contrast, non-canonical β-catenin independent Wnt signaling supports cardiac specification in different model systems including chicken and Xenopus embryos as well as murine and human embryonic stem cells (Chen et al., 2008; Eisenberg and Eisenberg, 1999; Mazzotta et al., 2016; Onizuka et al., 2012; Pandur et al., 2002; Rai et al., 2012; Terami et al., 2004; Ueno et al., 2007). Later in development, non-canonical Wnt signaling has been demonstrated to be required for terminal differentiation (Gessert et al., 2008; Hempel et al., 2017) and to be also involved in ventricular trabeculation, sarcomere formation and proper outflow tract development in mice (Nagy et al., 2010; Zhou et al., 2007) and Xenopus (Hempel et al., 2017).…”

RCSD1 expression associates with survival in triple negative breast cancer.

“…It is not understood why women of African descent (black women) are diagnosed with triple negative breast cancer more frequently than white women, and why this disease is more aggressive in black women. RCSD1 is a CapZ-interacting protein that functions in non-canonical Wnt pathway signaling (5). RCSD1 may be of relevance as a biomarker in identifying patients who are more likely to survive, perhaps as part of a panel of genes used for prognostic stratification, and the molecule itself may be important to the biology of triple negative breast cancer etiology or more likely its progression.…”

t(1;1)(q24;q25) RCSD1/ABL2::inv(1)(q24q25) RCSD1/ABL2

“…RCSD1 Binds CapZ to prevent CapZ from binding to the actin cytoskeleton. The T-cell costimulatory receptor CD28 phosphorylation regulates RCSD1 (Hempel et al 2017: Tian et al 2015.…”