Loss of Dis3l2 partially phenocopies Perlman syndrome in mice and results in up-regulation of Igf2 in nephron progenitor cells

Abstract

Loss of function of the DIS3L2 exoribonuclease is associated with Wilms tumor and the Perlman congenital overgrowth syndrome. LIN28, a Wilms tumor oncoprotein, triggers the DIS3L2-mediated degradation of the precursor of let-7, a microRNA that inhibits Wilms tumor development. These observations have led to speculation that DIS3L2-mediated tumor suppression is attributable to let-7 regulation. Here we examine new DIS3L2-deficient cell lines and mouse models, demonstrating that DIS3L2 loss has no effect on mature let-7 levels. Rather, analysis of -null nephron progenitor cells, a potential cell of origin of Wilms tumors, reveals up-regulation of, a growth-promoting gene strongly associated with Wilms tumorigenesis. These findings nominate a new potential mechanism underlying the pathology associated with DIS3L2 deficiency.

Tumour suppressor WT1 regulates the let-7-Igf1r axis in kidney mesenchyme

“…WT. Additionally, DIS3L2 has also been shown to be involved in the tumour biology by upregulating IGF2 expression(Hunter et al, 2018). Inagreement with this augmented IGF expression, we observe changes in Igf1r levels as a downstream event of let-7 downregulation.…”

“…The microRNA pathway has also been indirectly linked to WT. Recent studies have shown that the MIRPG-mutation associated with WTs also converge on the IGF signalling pathway through transcriptional mechanisms (Hunter et al, 2018). The Perlman overgrowth syndrome, characterized by an increased susceptibility to WT, arises because of mutations in the exoribonuclease DIS3L2, which is involved in degradation of oligouridylated transcripts, including microRNA let-7 (Astuti et al, 2012, Chang et al, 2013.…”

Dis3L2 regulates cellular proliferation through a PI3-Kinase dependent signalling pathway

“…Although previous studies have attempted to identify the proliferation pathways controlled by Dis3L2, many have used individual cells in culture rather than developing tissue which more accurately represents the physiological environment. A Dis3L2 knockout mouse model has demonstrated a transcriptional increase in insulin growth factor 2 (Igf2) mRNA, however, no overgrowth was observed (23). Therefore, the cellular pathways linking Dis3L2 with proliferation have remained obscure.…”

Overgrowth syndromes and pediatric cancers: how many roads lead to IGF2?

“…Work with animal models has provided evidence that increased IGF2 expression is an important contributing factor in both BWS and Wilms tumor (Caspary et al 1999;Hu et al 2011;Huang et al 2016). Two studies, Chen et al (2018) in this issue and Hunter et al (2018) in the previous issue of Genes & Development, highlight the significance of IGF2 up-regulation in the context of Perlman syndrome and Wilms tumor, respectively. Hunter et al (2018) addressed the mechanisms underlying Perlman syndrome, which is an autosomal recessive syndrome arising through mutation of DIS3L2 on chromosome 2q37 (Astuti et al 2012).…”

“…Two studies, Chen et al (2018) in this issue and Hunter et al (2018) in the previous issue of Genes & Development, highlight the significance of IGF2 up-regulation in the context of Perlman syndrome and Wilms tumor, respectively. Hunter et al (2018) addressed the mechanisms underlying Perlman syndrome, which is an autosomal recessive syndrome arising through mutation of DIS3L2 on chromosome 2q37 (Astuti et al 2012). DIS3L2 functions as a 3 ′ -5 ′ exoribonuclease that preferentially degrades oligouridylated RNAs (Lubas et al 2013).…”