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Wnt/β-catenin signaling regulates sequential fate decisions of murine cortical precursor cells


Draganova, Kalina; Zemke, Martina; Zurkirchen, Luis; Valenta, Tomas; Cantù, Claudio; Okoniewski, Michal; Schmid, Marie-Theres; Hoffmans, Raymond; Götz, Magdalena; Basler, Konrad; Sommer, Lukas (2015). Wnt/β-catenin signaling regulates sequential fate decisions of murine cortical precursor cells. Stem Cells, 33(1):170-182.

Abstract

The fate of neural progenitor cells (NPC) is determined by a complex interplay of intrinsic programs and extrinsic signals, very few of which are known. β-catenin transduces extracellular Wnt signals, but also maintains adherens junctions integrity. Here, we identify for the first time the contribution of β-catenin transcriptional activity as opposed to its adhesion role in the development of the cerebral cortex by combining a novel β-catenin mutant allele with conditional inactivation approaches. Wnt/β-catenin signaling ablation leads to premature NPC differentiation, but, in addition, to a change in progenitor cell cycle kinetics and an increase in basally dividing progenitors. Interestingly, Wnt/β-catenin signaling affects the sequential fate switch of progenitors, leading to a shortened neurogenic period with decreased number of both deep and upper-layer neurons and later, to precocious astrogenesis. Indeed, a genome-wide analysis highlighted the premature activation of a corticogenesis differentiation program in the Wnt/β-catenin signaling-ablated cortex. Thus, β-catenin signaling controls the expression of a set of genes that appear to act downstream of canonical Wnt signaling to regulate the stage-specific production of appropriate progenitor numbers, neuronal subpopulations, and astroglia in the forebrain. Stem Cells 2014.

Abstract

The fate of neural progenitor cells (NPC) is determined by a complex interplay of intrinsic programs and extrinsic signals, very few of which are known. β-catenin transduces extracellular Wnt signals, but also maintains adherens junctions integrity. Here, we identify for the first time the contribution of β-catenin transcriptional activity as opposed to its adhesion role in the development of the cerebral cortex by combining a novel β-catenin mutant allele with conditional inactivation approaches. Wnt/β-catenin signaling ablation leads to premature NPC differentiation, but, in addition, to a change in progenitor cell cycle kinetics and an increase in basally dividing progenitors. Interestingly, Wnt/β-catenin signaling affects the sequential fate switch of progenitors, leading to a shortened neurogenic period with decreased number of both deep and upper-layer neurons and later, to precocious astrogenesis. Indeed, a genome-wide analysis highlighted the premature activation of a corticogenesis differentiation program in the Wnt/β-catenin signaling-ablated cortex. Thus, β-catenin signaling controls the expression of a set of genes that appear to act downstream of canonical Wnt signaling to regulate the stage-specific production of appropriate progenitor numbers, neuronal subpopulations, and astroglia in the forebrain. Stem Cells 2014.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Anatomy
04 Faculty of Medicine > Functional Genomics Center Zurich
07 Faculty of Science > Institute of Molecular Life Sciences
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:Cellular proliferation; Neural differentiation; Neural stem cell; Signal transduction
Language:English
Date:January 2015
Deposited On:17 Nov 2014 09:44
Last Modified:05 Apr 2016 18:30
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:1066-5099
Publisher DOI:https://doi.org/10.1002/stem.1820
PubMed ID:25182747

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