SUMOylation controls stem cell proliferation and regional cell death through Hedgehog signaling in planarians

Abstract

Mechanisms underlying anteroposterior body axis differences during adult tissue maintenance and regeneration are poorly understood. Here, we identify that post-translational modifications through the SUMO (Small Ubiquitin-like Modifier) machinery are evolutionarily conserved in the Lophotrocozoan Schmidtea mediterranea. Disruption of SUMOylation in adult animals by RNA-interference of the only SUMO E2 conjugating enzyme Ubc9 leads to a systemic increase in DNA damage and a remarkable regional defect characterized by increased cell death and loss of the posterior half of the body. We identified that Ubc9 is mainly expressed in planarian stem cells (neoblasts) but it is also transcribed in differentiated cells including neurons. Regeneration in Ubc9(RNAi) animals is impaired and associated with low neoblast proliferation. We present evidence indicating that Ubc9-induced regional cell death is preceded by alterations in transcription and spatial expression of repressors and activators of the Hedgehog signaling pathway. Our results demonstrate that SUMOylation acts as a regional-specific cue to regulate cell fate during tissue renewal and regeneration.

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Acknowledgements

We thank Edelweiss Pfister for technical assistance and members of the Oviedo Lab for comments on the manuscript. We acknowledge Drs. Marcos Garcia-Ojeda and Anna Beaudin for assistance with FACS analysis and comments on the manuscript. Thanks are also extended to Ulrike Abu-Shach for technical assistance cloning Ubc9. The SYNORF antibody was obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH and maintained at the University of Iowa, Department of Biology. We are grateful to Sánchez Alvarado/Hawley labs for providing a sample of the SMED-RAD51 antibody.

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MT, PGB, AT, LB, and NJO performed research and analyzed data. MT, LB, and NJO wrote the manuscript. All authors read the manuscript, provided comments and approved the final version.

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Correspondence to Néstor J. Oviedo.

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The authors declare no competing or financial interest.

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We acknowledge support from University of California Merced and the Israel Science Foundation (ISF 1878/15) and the Israel Cancer Research Fund 14-101-PG to LB. This research was funded by the National Cancer Institute and National Institute of General Medical Sciences of the National Institute of Health, awards CA176114 and GM109372 to NJO.

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Thiruvalluvan, M., Barghouth, P.G., Tsur, A. et al. SUMOylation controls stem cell proliferation and regional cell death through Hedgehog signaling in planarians. Cell. Mol. Life Sci. 75, 1285–1301 (2018). https://doi.org/10.1007/s00018-017-2697-4

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Keywords

  • Ubc9
  • Regeneration
  • Genomic instability
  • Rad51
  • Patched