Somers, H. M. | bioRxiv Science

bioRxiv2025

Glucocorticoid and Mineralocorticoid Receptors Jointly Promote Vascular Development in Kidney Organoids

To examine the co-development of vasculature and renal epithelial tissue, we employed a human pluripotent stem cell-derived kidney organoid system. We found that cooperative signaling through the glucocorticoid receptor and mineralocorticoid receptor via hydrocortisone enabled rich endothelial cell differentiation and vessel formation. Bulk RNA sequencing analysis revealed that hydrocortisone perturbs an angiogenic transcriptional program early in development and promotes instead a pro-endothelial survival transcriptional program, with upregulation of angiopoietin 1 at both the mRNA and protein level. Additionally, we saw that hydrocortisone does not seem to significantly affect gene expression of canonical nephrogenic genes compared to our controls, suggesting its effect is largely restricted to endothelial cell differentiation. Our results show that kidney organoids offer a unique platform to study developmental signals that drive endothelial cell differentiation and vessel formation.

developmental biology↗

bioRxiv2025

Modified tau leads to neuronal and global ribosome dysfunction in C. elegans model of tauopathy

Alzheimers disease (AD) is a neurodegenerative disease characterized by an early loss of memory formation which requires protein synthesis. Tau is an intrinsically disordered protein and is subject to extensive post-translational modifications (PTMs). Some PTMs have been shown to alter localization of tau and allow tau to disrupt protein translation. Protein interactome studies indicate that tau might interact with ribosomal proteins. Therefore, we hypothesized that tau is causing ribosomal dysfunction as an early event and this interaction is dependent on taus PTMs. To test this, we used a C. elegans strain expressing single copy insertion of human tau as well as two of the most frequent modified versions of tau in mechanosensory neurons. With our assay to measure translation, we showed that in our T231 phosphorylation mimetic strain, there was a significant decrease in neuronal translation. This mimetic strain also showed a significant decrease in median lifespan and locomotion. Unexpectedly, in all our Tau-expressing strains, we detected a significant decrease in whole worm translation, suggesting a possible role of tau to influence translation in other tissues in worm. Our in vitro, in vivo and ex vivo efforts to demonstrate tau-ribosome association via fluorescent polysome profiling have shown that there is no direct association between tau and the ribosome. Ribosome dysfunction caused by modified tau could be an early event in AD pathology before the pathological hallmarks appear.

neuroscience↗