The effect of S427F mutation on RXRα activity depends on its dimeric partner.

RXRs are nuclear receptors acting as transcription regulators that control key cellular processes in all tissues. All type II nuclear receptors require RXRs for transcriptional activity by forming heterodimeric complexes. Recent whole-exome sequencing studies have identified the RXRα S427F hotspot mutation in 5% of the bladder cancer patients, which is always located at the interface of RXRα with its obligatory dimerization partners. Here, we show that mutation of S427 deregulates transcriptional activity of RXRα dimers, albeit with diverse allosteric mechanisms of action depending on its dimeric partner. S427F acts by allosteric mechanisms, which range from inducing the collapse of the binding pocket to allosteric stabilization of active co-activator competent RXRα states. Unexpectedly, RXR S427F heterodimerization leads to either loss- or gain-of-function complexes, in both cases likely compromising its tumor suppressor activity. This is the first report of a cancer-associated single amino acid substitution that affects the function of the mutant protein variably depending on its dimerization partner.

The Intestinal Epithelium - Fluid Fate and Rigid Structure From Crypt Bottom to Villus Tip.

The single-layered, simple epithelium of the gastro-intestinal tract controls nutrient uptake, coordinates our metabolism and shields us from pathogens. Despite its seemingly simple architecture, the intestinal lining consists of highly distinct cell populations that are continuously renewed by the same stem cell population. The need to maintain balanced diversity of cell types in an unceasingly regenerating tissue demands intricate mechanisms of spatial or temporal cell fate control. Recent advances in single-cell sequencing, spatio-temporal profiling and organoid technology have shed new light on the intricate micro-structure of the intestinal epithelium and on the mechanisms that maintain it. This led to the discovery of unexpected plasticity, zonation along the crypt-villus axis and new mechanism of self-organization. However, not only the epithelium, but also the underlying mesenchyme is distinctly structured. Several new studies have explored the intestinal stroma with single cell resolution and unveiled important interactions with the epithelium that are crucial for intestinal function and regeneration. In this review, we will discuss these recent findings and highlight the technologies that lead to their discovery. We will examine strengths and limitations of each approach and consider the wider impact of these results on our understanding of the intestine in health and disease.

Notch controls urothelial integrity in the mouse bladder.

The Notch signaling pathway mediates cell-cell communication regulating cell differentiation and proliferation and cell fate decisions in various tissues. In the urinary bladder, Notch acts as a tumor suppressor in mice, while mutations in Notch pathway components have been identified in human bladder cancer as well. Here we report that the genetic inactivation of Notch in mice leads to downregulation of cell-cell and cell-ECM interaction components, including proteins previously implicated in interstitial cystitis/bladder pain syndrome (IC/BPS), structural defects and mucosal sloughing, inflammation, and leaky urine-blood barrier. Molecular profiling of ailing mouse bladders showed similarities with IC/BPS patient tissue, which also presented low Notch pathway activity as indicated by reduced expression of canonical Notch targets. Urothelial integrity was reconstituted upon exogenous reactivation of the Notch pathway, implying a direct involvement of Notch. Despite damage and inflammation, urothelial cells failed to proliferate, uncovering a possible role for α4 integrin in urothelial homeostasis. Our data uncover a broad role for Notch in bladder homeostasis involving urothelial cell crosstalk with the microenvironment.