Abstract
Polycomb repressive complex 2 (PRC2) controls maintenance and lineage determination of stem cells by suppressing genes that regulate cellular differentiation and tissue development. However, the role of PRC2 in lineage-committed somatic cells is mostly unknown. Here we show that Eed deficiency in chondrocytes causes severe kyphosis and a growth defect with decreased chondrocyte proliferation, accelerated hypertrophic differentiation and cell death with reduced Hif1a expression. Eed deficiency also causes induction of multiple signalling pathways in chondrocytes. Wnt signalling overactivation is responsible for the accelerated hypertrophic differentiation and kyphosis, whereas the overactivation of TGF-β signalling is responsible for the reduced proliferation and growth defect. Thus, our study demonstrates that PRC2 has an important regulatory role in lineage-committed tissue cells by suppressing overactivation of multiple signalling pathways.
Highlights
Polycomb repressive complex 2 (PRC2) controls maintenance and lineage determination of stem cells by suppressing genes that regulate cellular differentiation and tissue development
In order to investigate the role of PRC2 in skeletal development, we ablated the Eed gene in chondrocytes using floxed Eed mice and Col2-Cre transgenic mice in which Cre recombinase is expressed under the control of a mouse Col2a1 promoter
The reduction in hypoxia-inducible transcription factor 1a (Hif1a) expression in Eed-deficient chondrocytes appeared to be mainly caused by a decrease in Hif1a mRNA. These findings suggest that transcriptional regulation of Hif1a by PRC2 is necessary for chondrocyte viability within the central region of the growth plate
Summary
Polycomb repressive complex 2 (PRC2) controls maintenance and lineage determination of stem cells by suppressing genes that regulate cellular differentiation and tissue development. Proliferation and differentiation of growth plate chondrocytes is tightly controlled by multiple signalling systems[3], including Indian hedgehog, parathyroid hormone-related peptide[1,4], fibroblast growth factor[2,5], C-type natriuretic peptide[6], insulin-like growth factor[7], bone morphogenetic protein, transforming growth factor-b (TGF-b)[8,9] and Wnt signalling[10,11]. These extracellular signalling molecules are further mediated by specific and common intracellular signalling pathways, including the mitogen-activated protein kinase and phosphoinositide 3 kinase pathways. We show that PRC2 has an essential role in regulating proliferation and differentiation of growth plate chondrocytes by suppressing multiple signalling pathways
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