Data from: Drosophila Sulf1 is required for the termination of intestinal stem cell division during regeneration

Stem cell division is activated to trigger regeneration in response to tissue damage. The molecular mechanisms by which this stem cell mitotic activity is properly repressed at the end of regeneration are poorly understood. Here we show that a specific modification of heparan sulfate (HS) is critical in regulating Drosophila intestinal stem cell (ISC) division during normal midgut homeostasis and regeneration. Loss of the extracellular HS endosulfatase Sulf1 results in increased ISC division during normal homeostasis, which is caused by upregulation of mitogenic signaling including the JAK/STAT, EGFR, and Hedgehog pathways. Using a regeneration model, we found that ISCs failed to properly halt division at the termination stage in Sulf1 mutants, showing that Sulf1 is required for terminating ISC division at the end of regeneration. We propose that post-transcriptional regulation of mitogen signaling by HS structural modifications provides a novel regulatory step for precise temporal control of stem cell activity during regeneration.

组织损伤后，干细胞分裂会被激活以启动再生过程。目前，关于再生结束阶段如何精准抑制干细胞有丝分裂活性的分子机制，仍不甚明晰。本研究证实，硫酸乙酰肝素（heparan sulfate，HS）的特定修饰，在果蝇正常中肠稳态与再生过程中，对果蝇肠道干细胞（Drosophila intestinal stem cell，ISC）的分裂调控发挥关键作用。细胞外硫酸乙酰肝素内切硫酸酯酶Sulf1的缺失，会导致正常稳态下ISC分裂水平升高，该现象由JAK/STAT、EGFR及Hedgehog等促有丝分裂信号通路的上调所介导。利用再生模型开展实验后，我们发现Sulf1突变体中的ISC无法在再生终止阶段正常停止分裂，由此证明Sulf1是再生结束时终止ISC分裂的必需因子。我们据此提出，通过HS的结构修饰对促有丝分裂信号进行转录后调控，为再生过程中干细胞活性的精准时序控制提供了全新的调控途径。