Biology subjects

Hastie, N.

Publications and source records attributed to Hastie, N..

3 recordsLinked to original sources

bioRxiv2025

Tumour suppressor WT1 and its interacting protein RNA helicase DDX5 regulate the microRNA let7/Igf1r axis in the kidney mesenchyme

Germline mutations in tumour suppressor, Wilms Tumour 1 (WT1) as well as somatic and germline mutations in microRNA processing genes (MIRPG) have been identified in Wilms Tumours (WT), where upregulation of IGF2 through genetic and/or epigenetic mechanisms is commonly seen. Whether these different epigenetic and genetic causes converge on common targets is still unclear. WT1 is also involved in RNA binding and regulates the stability of these developmental mRNAs. We now show that WT1 interacts with microRNA let-7 and proteins involved in microRNA processing wherein DDX5 is found to be an important regulator. WT1 absence results in decreased microRNA levels in cell lines and kidney mesenchyme, which is further downregulated in a WT1 and DDX5 double knockdown, ultimately modulating Igf1r expression. These findings suggest a plausible mechanism by which WT1 mutations lead to WT, and converge on microRNA pathway and IGF signalling pathway, which are important contributing factors in the aetiology of WT.

cancer biology↗

bioRxiv2020

Wt1-expressing cells contribute to mesoderm-derived tissues in intestine and mesentery in two distinct phases during murine embryonic development.

Previously, genetic lineage tracing based on the mesothelial marker Wt1, appeared to show that peritoneal mesothelial cells have a range of differentiative capacities and are the direct progenitors of vascular smooth muscle in the intestine. However, it was not clear whether this was a temporally limited process or continued throughout postnatal life. Here, using a conditional Wt1-based genetic lineage tracing approach, we demonstrate that the postnatal and adult peritoneum covering intestine, mesentery and body wall only maintained itself and failed to contribute to other visceral tissues. Pulse-chase experiments of up to 6 months revealed that Wt1-expressing cells remained confined to the peritoneum and failed to differentiate into cellular components of blood vessels or other tissues underlying the peritoneum. Ablation of Wt1 in adult mice did not result in changes to the intestinal wall architecture. In the heart, we observed that Wt1-expressing cells maintained the epicardium and contributed to coronary vessels in newborn and adult mice. Our results demonstrate that Wt1-expressing cells in the peritoneum have limited differentiation capacities, and that contribution of Wt1-expressing cells to cardiac vasculature is based on organ-specific mechanisms.

developmental biology↗

bioRxiv2019

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

Wilms tumour 1 (WT1) is a transcription factor and a tumour suppressor, essential for the development and homeostasis of multiple tissues derived from the intermediate and lateral plate mesoderm. Germline WT1 mutations result in the eponymous paediatric kidney cancer, genitourinary anomalies and in some cases congenital diaphragmatic hernia One common feature in Wilms Tumours (WT), is upregulation of IGF2 through genetic and/or epigenetic mechanisms. Recent studies have identified both somatic and germline mutations in microRNA processing genes (MIRPG) in WT. Whether these different epigenetic and genetic causes converge on common targets and the mechanisms by which they act are still unclear. WT1 is involved in RNA binding and regulates the RNA stability of important developmental genes. We now show that WT1 interacts with let-7 family of microRNAs, and the absence of WT1 results in reduced levels of mature microRNA in cell lines and kidney mesenchyme. As a consequence, let-7 targets, including Igf1 receptor (Igf1r), are upregulated in the absence of Wt1, thus confirming the presence of a WT1-let7-Igf1r axis. These findings suggest a possible mechanism by which WT1 mutations lead to WT, and reinforce the idea that the perturbation of the microRNA and IGF signalling pathways are important contributing factors in the aetiology of WT.

cancer biology↗