Dataset Information

Disparate levels of beta-catenin activity determine nephron progenitor cell fate.

ABSTRACT: Formation of a functional kidney depends on the balance between renewal and differentiation of nephron progenitors. Failure to sustain this balance can lead to kidney failure or stem cell tumors. For nearly 60 years, we have known that signals from an epithelial structure known as the ureteric bud were essential for maintaining this balance. More recently it was discovered that one molecule, Wnt9b, was necessary for both renewal and differentiation of the nephron progenitor cells. How one ligand signaling through one transcription factor promoted two seemingly contradictory cellular processes was unclear. In this study, we show that Wnt9b/beta-catenin signaling alone is sufficient to promote both renewal and differentiation. Moreover, we show that discrete levels of beta-catenin can promote these two disparate fates, with low levels fostering progenitor renewal and high levels driving differentiation. These results provide insight into how Wnt9b regulates distinct target genes that balance nephron progenitor renewal and differentiation.

SUBMITTER: Ramalingam H

PROVIDER: S-EPMC5988999 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Disparate levels of beta-catenin activity determine nephron progenitor cell fate.

Ramalingam Harini H Fessler Alicia R AR Das Amrita A Valerius M Todd MT Basta Jeannine J Robbins Lynn L Brown Aaron C AC Oxburgh Leif L McMahon Andrew P AP Rauchman Michael M Carroll Thomas J TJ

Developmental biology 20180426 1

Formation of a functional kidney depends on the balance between renewal and differentiation of nephron progenitors. Failure to sustain this balance can lead to kidney failure or stem cell tumors. For nearly 60 years, we have known that signals from an epithelial structure known as the ureteric bud were essential for maintaining this balance. More recently it was discovered that one molecule, Wnt9b, was necessary for both renewal and differentiation of the nephron progenitor cells. How one ligand ...[more]

PMID: 29705331

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Project description:Canonical WNT/?-catenin signaling is a central pathway in embryonic development, but it is also connected to a number of cancers and developmental disorders. Here we apply a combined in-vitro and in-silico approach to investigate the spatio-temporal regulation of WNT/?-catenin signaling during the early neural differentiation process of human neural progenitors cells (hNPCs), which form a new prospect for replacement therapies in the context of neurodegenerative diseases. Experimental measurements indicate a second signal mechanism, in addition to canonical WNT signaling, being involved in the regulation of nuclear ?-catenin levels during the cell fate commitment phase of neural differentiation. We find that the biphasic activation of ?-catenin signaling observed experimentally can only be explained through a model that combines Reactive Oxygen Species (ROS) and raft dependent WNT/?-catenin signaling. Accordingly after initiation of differentiation endogenous ROS activates DVL in a redox-dependent manner leading to a transient activation of down-stream ?-catenin signaling, followed by continuous auto/paracrine WNT signaling, which crucially depends on lipid rafts. Our simulation studies further illustrate the elaborate spatio-temporal regulation of DVL, which, depending on its concentration and localization, may either act as direct inducer of the transient ROS/?-catenin signal or as amplifier during continuous auto-/parcrine WNT/?-catenin signaling. In addition we provide the first stochastic computational model of WNT/?-catenin signaling that combines membrane-related and intracellular processes, including lipid rafts/receptor dynamics as well as WNT- and ROS-dependent ?-catenin activation. The model's predictive ability is demonstrated under a wide range of varying conditions for in-vitro and in-silico reference data sets. Our in-silico approach is realized in a multi-level rule-based language, that facilitates the extension and modification of the model. Thus, our results provide both new insights and means to further our understanding of canonical WNT/?-catenin signaling and the role of ROS as intracellular signaling mediator.

Dataset Information

Disparate levels of beta-catenin activity determine nephron progenitor cell fate.

Publications

Disparate levels of beta-catenin activity determine nephron progenitor cell fate.

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