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 is crucial for regulating Drosophila intestinal stem cell (ISC) division during normal midgut homeostasis and regeneration. Loss of the extracellular heparan sulfate endosulfatase Sulf1 resulted in increased ISC division during normal homeostasis, which was caused by upregulation of mitogenic signaling including the JAKSTAT, 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 posttranscriptional regulation of mitogen signaling by heparan sulfate structural modifications provides a new regulatory step for precise temporal control of stem cell activity during regeneration.
Bibliographical noteFunding Information:
We thank Melissa Harrison, KateO'Connor-Giles, Jill Wildonger, Michael O'Connor, Huaqi Jiang, Tetsuya Tabata, Thomas Neufeld, Takashi Adachi-Yamada, BDSC (NIH P40OD018537), DGRC, the TRiP at Harvard Medical School (NIH R01 GM084947), and VDRC for reagents. We are grateful to Katsufumi Dejima and Emiko Tomiyasu for technical support.We also thank Daniel Levings and Andy Toth for helpful comments on the manuscript. This work was supported by the National Institutes of Health (R01 GM115099 to H.N.). M.T. held postdoctoral fellowships from the Japan Society for the Promotion of Science and the Uehara Memorial Foundation. Deposited in PMC for release after 12 months.
© 2017. Published by The Company of Biologists Ltd.
- Heparan sulfate proteoglycan