journal.pgen.1009297.pdf (3.77 MB)
Dis3L2 regulates cell proliferation and tissue growth though a conserved mechanism
journal contribution
posted on 2023-06-09, 22:32 authored by Benjamin TowlerBenjamin Towler, Amy L Pashler, Hope HaimeHope Haime, Katarzyna M Przybyl, Sandra C Viegas, Rute G Matos, Simon Morley, Cecilia M Arraiano, Sarah NewburySarah NewburyDis3L2 is a highly conserved 3’-5’ exoribonuclease which is mutated in the human overgrowth disorders Perlman syndrome and Wilms’ tumour of the kidney. Using Drosophila melanogaster as a model system, we have generated a new dis3L2 null mutant together with wild-type and nuclease-dead genetic lines in Drosophila to demonstrate that the catalytic activity of Dis3L2 is required to control cell proliferation. To understand the cellular pathways regulated by Dis3L2 to control proliferation, we used RNA-seq on dis3L2 mutant wing discs to show that the imaginal disc growth factor Idgf2 is responsible for driving the wing overgrowth. IDGFs are conserved proteins homologous to human chitinase-like proteins such as CHI3L1/YKL-40 which are implicated in tissue regeneration as well as cancers including colon cancer and non-small cell lung cancer. We also demonstrate that loss of DIS3L2 in human kidney HEK-293T cells results in cell proliferation, illustrating the conservation of this important cell proliferation pathway. Using these human cells, we show that loss of DIS3L2 results in an increase in the PI3-Kinase/AKT signalling pathway, which we subsequently show to contribute towards the proliferation phenotype in Drosophila. Our work therefore provides the first mechanistic explanation for DIS3L2-induced overgrowth in humans and flies and identifies an ancient proliferation pathway controlled by Dis3L2 to regulate cell proliferation and tissue growth.
Funding
Dissecting the cellular pathways controlled by the exoribonuclease Dis3L2 in growth regulation; G2431; BIOCHEMICAL SOCIETY
Understanding the cellular pathways regulated by Dis3L2 in cell proliferation; G2236; BBSRC-BIOTECHNOLOGY & BIOLOGICAL SCIENCES RESEARCH COUNCIL; BB/P021042/1
History
Publication status
- Published
File Version
- Published version
Journal
PLOS GeneticsISSN
1553-7390Publisher
Public Library of ScienceExternal DOI
Issue
12Volume
16Page range
1-29Article number
a1009297Department affiliated with
- Clinical and Experimental Medicine Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2020-12-18First Open Access (FOA) Date
2021-01-12First Compliant Deposit (FCD) Date
2020-12-18Usage metrics
Categories
No categories selectedKeywords
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC