Abstract
Nearly three decades ago, the Wilms’ tumor suppressor Wt1 was identified as a crucial regulator of heart development. Wt1 is a zinc finger transcription factor with multiple biological functions, implicated in the development of several organ systems, among them cardiovascular structures. This review summarizes the results from many research groups which allowed to establish a relevant function for Wt1 in cardiac development and disease. During development, Wt1 is involved in fundamental processes as the formation of the epicardium, epicardial epithelial-mesenchymal transition, coronary vessel development, valve formation, organization of the cardiac autonomous nervous system, and formation of the cardiac ventricles. Wt1 is further implicated in cardiac disease and repair in adult life. We summarize here the current knowledge about expression and function of Wt1 in heart development and disease and point out controversies to further stimulate additional research in the areas of cardiac development and pathophysiology. As re-activation of developmental programs is considered as paradigm for regeneration in response to injury, understanding of these processes and the molecules involved therein is essential for the development of therapeutic strategies, which we discuss on the example of WT1.
Highlights
The Wilms’ tumor 1 (WT1) gene was originally identified based on its mutational inactivation in Wilms’ tumor [1,2,3]
They revealed expression of neuronal markers in the epicardium during early cardiac development, notably of tubulin beta-3 chain (Tubb3), which was colocalized with Wilms’ tumor suppressor 1 (Wt1) in epicardium and the nervous system, neural cell adhesion molecule (Ncam), and the β2 adrenergic receptor (β2AR)
Apart from hypoxia and direct transcriptional activation by hypoxia inducible factor 1 (HIF-1) [100], which are likely to be involved in cardiac development and repair, Hippo signaling components have been proposed to regulate Wt1 expression, epicardial epithelial mesenchymal transition (EMT) and epicardial cell proliferation and differentiation into coronary endothelial cells [183]
Summary
The Wilms’ tumor 1 (WT1) gene was originally identified based on its mutational inactivation in Wilms’ tumor (nephroblastoma) [1,2,3]. Wt1-expressing proepicardial cells contact the dorsal wall of the heart from which the proepicardial cell migrate over the myocardium of the heart tube to form the epicardial layer by E12.5 [23,24]. This view has been challenged recently by the detection of a common progenitor cell population of epicardium and myocardium using single-cell RNA sequencing [25]. How these common progenitors might migrate during cardiac development is currently an open question. We indicate emerging notions and point out problems and promises in the field of development of therapeutic strategies for cardiac repair
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