In Vivo Clonal Analysis Reveals Lineage-Restricted Progenitor Characteristics in Mammalian Kidney Development, Maintenance, and Regeneration

Abstract

Summary The mechanism and magnitude, by which the mammalian kidney generates and maintains its proximal tubules, distal tubules, and collecting ducts, remain controversial. Here we utilized long-term in-vivo genetic lineage tracing and clonal analysis of individual cells from kidneys undergoing development, maintenance, and regeneration. We show that the adult mammalian kidney undergoes continuous tubulogenesis via expansions of fate-restricted clones. Kidneys recovering from damage undergo tubulogenesis through expansions of clones with segment-specific borders, and renal spheres developing in-vitro from individual cells maintain distinct, segment-specific fates. Analysis of mice derived by transfer of color-marked ES cells into uncolored blastocysts demonstrates that nephrons are polyclonal, developing from expansions of singly fated clones. Finally, we show that adult renal clones are derived from Wnt responsive precursors, and their tracing in-vivo generates tubules that are segment-specific. Collectively, these analysis demonstrates that fate-restricted precursors functioning as unipotent progenitors continuously maintain and self-preserve the mouse kidney throughout life.

Combined Deletion of Vhl and Kif3a Accelerates Renal Cyst Formation

“…Cellular proliferation after damage to nephrons triggers cyst formation in adult kidneys that lack a variety of cyst-predisposing genes. 21,23 We suggest that the low rate of continuous cell turnover in the adult kidney 31 is the trigger for initiation of cyst formation by Kif3a-or Vhl/Kif3a-deficient cells, with the latter genotype being more sensitized than the former to initiate cyst formation. We observed no increase in proliferation rate of Vhl/Kif3a mutant cells at an early time point after gene deletion, arguing that the increased initiation of cyst formation is not due to alteration in the rate of cellular turnover.…”

Role of adenylyl cyclase 6 in the development of lithium-induced nephrogenic diabetes insipidus

“…However, based on the current data, it is plausible that AC6 plays distinctive roles in epithelial cell proliferation and may even be a determinant of the conversion of PC to IC (45). Examination of Li + effects in cell lineage-tracing models, or such models with an AC6-deficient background, would be a powerful approach to examine these possibilities (46,47).…”

Female mice lacking Xist RNA show partial dosage compensation and survive to term

“…S6A,B). In mice, postnatal developmental staging could be performed using the kidney, where the nephrogenic zone (consisting of immature glomeruli and nephrons undergoing proliferation) at P1 normally gives way to mature cortex and fully formed glomeruli by P23 (Little et al 2007;Rinkevich et al 2014;Romagnani et al 2015). This postnatal transition occurred in the kidneys of both mutant and control females (Fig.…”