Every Beat You Take—The Wilms′ Tumor Suppressor WT1 and the Heart

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.

Dynamic Spatiotemporal Expression Pattern of the Senescence-Associated Factor p16Ink4a in Development and Aging

“…At the same time, p19 and p21 did not show such a remarkable variation of expression. We limited the current study to the investigation of brain, heart, kidney, and liver as these organs already develop at the embryonic time points chosen [65][66][67][68] and are relatively easy to isolate. Nevertheless, it is possible that p16, p19, and p21 might be expressed in a variety of developing organs.…”

The Senescence Markers p16INK4A, p14ARF/p19ARF, and p21 in Organ Development and Homeostasis

“…We determined p16INK4A expression between embryonic day (E10) and birth, at postnatal day seven (P7), postnatal day 21, which corresponds to weaning, in adults, and 16–18-month-old mice. We focused on the heart, brain, liver, and kidney as these organs or progenitors are already present at the first time point chosen [ 116 , 117 , 118 , 119 ]. p16INK4A, p14ARF/p19ARF, and p21 were detectable at all investigated embryonic and postnatal time points.…”

“…Maintenance of cardiac function during aging and cardiac remodeling had to some extent been attributed to the expansion and differentiation of cardiac-resident stem cells (reviewed in [ 197 ]). To which extent cardiac stem and progenitor cells contribute to myocytes, endothelium, smooth muscle cells, etc., in cardiac repair is still a matter of debate [ 111 , 117 , 197 , 231 , 232 , 233 , 234 ]. In contrast to earlier publications, it is now widely accepted that cardiac, but not hematopoietic-derived progenitor cells are implicated in the cardiac repair [ 235 ].…”

Spatiotemporal development and the regulatory mechanisms of cardiac resident macrophages: Contribution in cardiac development and steady state

“…Specific deletion of WT1 + mesothelial cells resulted in significant reductions in macrophage populations with residual cells exhibiting morphological changes, which affected the growth of tissue tumors, suggesting that WT1 + endothelial cells could affect tissue homeostasis by controlling the recruitment and development of macrophages 69 . Additionally, WT1 plays a crucial role in regulating the migration of YS‐Macs to the heart 70 . The expression pattern of WT1 in the fetal heart is similar to the order of appearance of CRMs in the heart.…”