Abstract
ABSTRACTA correct balance between proliferative and asymmetric cell divisions underlies normal development, stem cell maintenance and tissue homeostasis. What determines whether cells undergo symmetric or asymmetric cell division is poorly understood. To gain insight into the mechanisms involved, we studied the stem cell-like seam cells in the Caenorhabditis elegans epidermis. Seam cells go through a reproducible pattern of asymmetric divisions, instructed by divergent canonical Wnt/β-catenin signaling, and symmetric divisions that increase the seam cell number. Using time-lapse fluorescence microscopy we observed that symmetric cell divisions maintain asymmetric localization of Wnt/β-catenin pathway components. Our observations, based on lineage-specific knockout and GFP-tagging of endogenous pop-1, support the model that POP-1TCF induces differentiation at a high nuclear level, whereas low nuclear POP-1 promotes seam cell self-renewal. Before symmetric division, the transcriptional regulator RNT-1Runx and cofactor BRO-1CBFβ temporarily bypass Wnt/β-catenin asymmetry by downregulating pop-1 expression. Thereby, RNT-1/BRO-1 appears to render POP-1 below the level required for its repressor function, which converts differentiation into self-renewal. Thus, we found that conserved Runx/CBFβ-type stem cell regulators switch asymmetric to proliferative cell division by opposing TCF-related transcriptional repression.
Highlights
Tissue-specific stem cells combine long-term maintenance with the generation of differentiating daughter cells
Wnt components localize asymmetrically in symmetric seam cell divisions We studied the stem cell-like precursors of the C. elegans epidermis to reveal the mechanisms that determine whether cells undergo symmetric or asymmetric cell divisions
The combined observations indicate that the transcriptional activator function of POP-1 is less crucial than its repressor function, and requires a limited amount of POP-1
Summary
Tissue-specific stem cells combine long-term maintenance with the generation of differentiating daughter cells. This can be achieved by intrinsically asymmetric cell divisions that simultaneously generate a self-renewing stem cell and a daughter cell that initiates a differentiation program (reviewed by Knoblich, 2010). Requires symmetric divisions that generate two self-renewing stem cells. The proper balance between symmetric ( proliferative) and asymmetric divisions is key to the development and maintenance of tissues, and to preventing tumor formation or premature differentiation. How stem and progenitor cells are instructed to switch between asymmetric and symmetric division modes remains largely unknown
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