ETS2 repressor factor (ERF) haploinsufficiency causes late onset craniosynostosis (OMIM 600775; CRS4) in humans while in mice Erf-insufficiency also leads to a similar multi-suture synostosis phenotype preceded by mildly reduced calvarium ossification. However, neither the cell types affected nor the effects per se have been identified so far. Here we establish an ex vivo system for the expansion of suture-derived mesenchymal stem and progenitor cells (sdMSCs) and analyze the role of Erf levels in their differentiation. Cellular data suggest that Erf-insufficiency specifically decreases osteogenic differentiation of sdMSCs resulting in the initially delayed mineralization of the calvarium. Transcriptome analysis indicates that Erf is required for efficient osteogenic lineage commitment of sdMSCs. Elevated retinoic acid catabolism due to increased levels of the cytochrome P450 superfamily member Cyp26b1 as a result of decreased Erf levels appears to be the underlying mechanism leading to defective differentiation. Exogenous addition of retinoic acid can rescue the osteogenic differentiation defect suggesting that Erf affects cranial bone mineralization during skull development through retinoic acid gradient regulation

中文翻译：

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Erf通过视黄酸途径影响颅缝骨祖细胞的定型和分化

ETS2 抑制因子 (ERF) 单倍体不足会导致人类迟发性颅缝早闭 (OMIM 600775; CRS4)，而在小鼠中，Erf 不足也会导致类似的多缝线缝早闭表型，随后颅骨骨化轻度减少。然而，到目前为止，尚未确定受影响的细胞类型和影响本身。在这里我们建立一个离体用于扩增缝线间充质干细胞和祖细胞 (sdMSCs) 的系统并分析 Erf 水平在其分化中的作用。细胞数据表明，Erf 不足会特异性降低 sdMSCs 的成骨分化，导致颅骨最初延迟矿化。转录组分析表明，Erf 是 sdMSCs 有效成骨谱系定型所必需的。由于细胞色素 P450 超家族成员Cyp26b1水平升高，维甲酸分解代谢升高由于降低的 Erf 水平似乎是导致分化缺陷的潜在机制。外源性添加维甲酸可以挽救成骨分化缺陷，表明 Erf 通过维甲酸梯度调节影响颅骨发育过程中的颅骨矿化