Cell & Developmental Biology
Open Access

Rebecca A. Wingert

Biography

Research Interest

The Wingert Lab studies the genetic and molecular mechanisms that control how renal stem cells accomplish kidney formation, impact kidney homeostasis, and facilitate kidney regeneration following organ injury. Understanding these processes has broad implications for identifying the basis of renal birth defects and the responses to tissue damage that lead to kidney disease. Kidney diseases are a growing global healthcare issue: they affect epidemic numbers of children and adults worldwide, and are steadily climbing in incidence. Kidney diseases can be treated with renal replacement through dialysis or organ transplant, but both strategies require life-long medical management and can involve significant complications. Knowledge obtained from studying the basic biology of the renal system can provide a valuable way to discover innovative therapies for kidney disorders.

Research in the Wingert Lab centers around two major areas:

Kidney Development Research: How do renal stem cells arise during development? How are nephrons constructed from renal stem/progenitor precursors? We are seeking to identify the genetic requirements for making renal cells. We utilize classical forward genetic screening and chemical genetics to study the molecules that affect in nephron formation. One benefit of these integrated approaches is that we can discover essential genes and signaling pathways that have never been implicated in renal progenitor biology. In addition, we perform expression studies to identify factors expressed by kidney cells during nephrogenesis, then assign their functional roles using reverse genetics, including knockdown and genome targeting strategies, as well as overexpression techniques to examine gain-of-function.
Kidney Regeneration and Aging Research: How can damaged nephron components be replaced? Are there renal stem cells that can facilitate treatment of renal diseases? Can differentiated nephron cells be induced to regenerate damaged nephrons? Can the activation of kidney developmental pathways facilitate regeneration? How does the kidney age, and is the aging of renal stem cells a contributing factor to the incidence of kidney disease? We are using models of nephron injury in the embryo and adult zebrafish to discover the cell and molecular events that are required for nephron regeneration during the lifetime of the animal. Along with our nephron development studies, it is our hope that these lines of inquiry will shed novel insights into the activities of kidney cells and guide the creation of new therapeutics.
While kidney diseases are diverse in origin, many share a common aspect: alterations to the basic unit of the kidney called the nephron. Each nephron is an epithelial tube that is highly specialized to excrete metabolic waste. Nephrons contain a blood filter that collects fluid from the circulation and a long tubule that consists of a series of segments with different epithelial cell types. Nephron segments perform discrete tasks in modifying the filtrate by reabsorbing and secreting solutes—jobs that enable the retention of desirable nutrients and export of metabolic wastes. Human kidneys are architecturally complex because they contain many nephrons (ranging from several hundred thousand to over one million) that have intricate loops and convolutions, and are organized in arbor-like arrays. The signaling pathways that control how renal stem cells give rise to nephrons during kidney development are poorly understood. Part of the reason for this is that the architecture and internal location of the kidney pose challenges for studying nephron development and dysfunction in mammals. For some time, there has been experimental evidence that the kidney exhibits a limited capacity to regenerate. Damage to epithelial cells in nephrons can be followed by a local regenerative response in which new nephron epithelial cells are made. However, the molecular mechanisms that enable this type of nephron regeneration remain largely enigmatic, and their discovery is hampered by the aforementioned limitations of existing mammalian models.

To study how nephrons are made during development and regeneration, we use the zebrafish, Danio rerio. The zebrafish is an outstanding model for kidney research for numerous reasons. First, zebrafish are a vertebrate species and share many similarities with more complex vertebrates like mammals. For example, there is a high degree of conservation between gene function and basic cellular processes between zebrafish and mammals. Zebrafish embryos develop outside the mother and are optically transparent, enabling the direct visualization of organ development. The embryo forms an anatomically simple kidney that is made up of two nephrons, while the zebrafish adult kidney displays complex nephron arrangements analogous to other higher vertebrates. Zebrafish nephrons are comprised of segments with epithelial cells that share gene expression signatures and ultrastructural traits with the segments that typify vertebrate nephrons. Importantly, there is a diverse arsenal of molecular tools now available to the zebrafish researcher, and these enable high-resolution study of cell biology and genetic analysis.