Abstract
The differentiation of the lateral plate mesoderm cells into heart field cells constitutes a critical step in the development of cardiac tissue and the genesis of functional cardiomyocytes. Hippo signaling controls cardiomyocyte proliferation, but the role of Hippo signaling during early cardiogenesis remains unclear. Here, we show that Hippo signaling regulates atrial cell number by specifying the developmental potential of cells within the anterior lateral plate mesoderm (ALPM), which are incorporated into the venous pole of the heart tube and ultimately into the atrium of the heart. We demonstrate that Hippo signaling acts through large tumor suppressor kinase 1/2 to modulate BMP signaling and the expression of hand2, a key transcription factor that is involved in the differentiation of atrial cardiomyocytes. Collectively, these results demonstrate that Hippo signaling defines venous pole cardiomyocyte number by modulating both the number and the identity of the ALPM cells that will populate the atrium of the heart.
Highlights
The human heart typically has about 2 billion cardiomyocytes (CMs) (Adler and Costabel, 1975; Laflamme and Murry, 2011), which together form the muscle layer of the heart responsible for contraction
We demonstrate that Large tumour suppressor kinase 1 and 2 (Lats1/2)-Yes-associated protein 1 (Yap1)/WW-domain-containing transcription regulator 1 (Wwtr1)-regulated Hippo signaling determines the number of secondary heart field (SHF) cells in the venous pole that originate from the caudal part of the anterior lateral plate mesoderm (ALPM)
We examined whether Yap1/Wwtr1 regulate the expression of transcription factors nkx2.5, hand2, and gata4, all of which are essential for early cardiac precursor cells (CPCs) differentiation (Schoenebeck et al, 2007). qPCR revealed that hand2 mRNA expression was significantly upregulated (Figure 3A and Figure 3—source data 1) and that nkx2.5 and gata4 mRNAs expression was unaffected in the lats1/2 morphants (Figure 3A and Figure 3—source data 1)
Summary
The human heart typically has about 2 billion cardiomyocytes (CMs) (Adler and Costabel, 1975; Laflamme and Murry, 2011), which together form the muscle layer of the heart responsible for contraction. The determination of the final number of CMs in the different parts of the heart involves highly coordinated processes of cell fate specification and proliferation during development. Understanding the relative contributions of these processes during the different stages of cardiac morphogenesis, as well as the mechanisms behind them, is one of the long-standing goals of the cardiac development field. Mammalian heart morphogenesis is best studied in the mouse. A bilateral group of cells in the splanchnic mesoderm specifies into cardiac precursor cells (CPCs) (Saga et al, 1999) and forms the first heart field (FHF). Cells of the FHF extend toward the midline to form a crescent-shaped epithelium, known as the cardiac crescent. CPCs from the secondary heart field (SHF), Fukui et al eLife 2018;7:e29106.
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