Kidney-specific deletion of the BicC family RNA-binding protein 1 triggers an ADPKD-like cystogenic program

PKD1 upstream open reading frames affect Polycystin-1 expression and polycystic kidney disease phenotypes.

Autosomal dominant polycystic kidney disease (ADPKD) accounts for 5-10% of prevalent end-stage kidney failure (ESKD). ADPKD cysts result from a loss of sufficient functional expression of PKD1/Polycystin-1 (PC1) in approximately 80% of families. Kidney disease severity correlates with the extent to which PC1 dosage is reduced below a critical level, and evidence suggests therapeutic benefit from increasing PC1 expression in these conditions. Upstream open reading frame (uORF) translation can reduce translation of a protein's coding sequence. Ribosome profiling data and bioinformatic predictions suggested the presence of conserved PKD1 uORFs, so we sought to explore their biological role. We generated luciferase reporters and two humanized PKD1 5'UTR mouse models with or without single nucleotide edits removing uORF start codons ("delta-uORF") to define active uORFs and test their impact on PC1 translation. PKD1 uORF start codons can robustly initiate translation and delta-uORF conveys a 2-4-fold increase in PC1 protein expression and resultant prevention of kidney cysts in Dnajb11 as well as in Pkd1 missense models. PKD1 uORF1-blocking steric antisense oligonucleotides (ASOs) substantially increase PC1 expression in vitro. PKD1 uORFs play an important role in the low basal expression of wild-type PKD1, and their inhibition represents an opportunity to therapeutically increase PC1 translation in polycystic kidney and liver disease resulting from reduced dosage of PC1.

A C. elegans model for functional analysis of conserved ADPKD variants in cilia, extracellular vesicles, and sensory signaling.

It is concluded that PC2C331S may perturb protein stability and/or polycystin complex formation prior to ciliary/EV trafficking and a C. elegans pipeline for mechanistic classification of conserved ADPKD-associated missense variants is established.

An integrin beta-1-anchored bicaudal C1-polycystin-1 module essential for tubular morphogenesis in polycystic kidney disease

Summary Genetic variants in the RNA-binding protein bicaudal C1 (BICC1) have been linked to very-early-onset polycystic kidney disease (PKD). This study identifies a crucial integrin-beta1 (ITGB1)-BICC1-polycystin-1 (PC1) complex that regulates F-actin organization and cell adhesion in human kidney cells through the expression of filamin-binding-LIM-protein-1 (FBLIM1). Both Bicc1 and Pkd1 knockout cells exhibit abnormal F-actin structure, increased cell stiffness, decreased adhesion and impaired migration while inhibiting F-actin branching directly triggers cyst formation. Locally, BICC1 interacts with F-actin, ITGB1, and FBLIM1 at focal adhesions. ITGB1 knockdown reduces surface BICC1 expression. In turn, BICC1 stabilizes FBLIM1 by influencing transcript abundance, promoting its local translation, and protecting it from degradation in the presence of PC1. In summary, these findings reveal a novel model of cystogenesis linking BICC1’s dual RNA and protein regulatory functions to the maintenance of cytoskeletal and tubular integrity.

The absence of Trim28 in nephron progenitors results in impaired kidney development and function

ABSTRACT The TRIM28 gene encodes a transcriptional regulator involved in a variety of molecular processes. Inactivation of TRIM28 has been linked to the epithelial subtype of Wilms tumor, the most common pediatric renal malignancy. Therefore, TRIM28 may impact early kidney morphogenesis. To investigate its role in nephrogenesis, we analyzed Trim28 conditional knockout (Trim28Δ/Δ) mice. We found that deleting Trim28 in nephron progenitors resulted in early postnatal lethality and reduced kidney weight. While all renal structures were present, the proximal tubules (PTs) were disorganized. Transcriptome analyses revealed cell type-specific deregulation of retroelement expression following Trim28 deletion. Further analysis of scRNA-seq data revealed a decreased frequency of nephron progenitor cells (NPCs), an increase in PT cells and a clear shift towards inflammatory gene expression patterns. While there was no evidence of tumor formation in Trim28Δ/Δ kidneys, the differentially expressed genes in Trim28Δ/Δ progenitors reflected reduced translation, similar to patterns observed in TRIM28 mutant tumor-derived NPCs. Thus, our data demonstrate that TRIM28 primarily influences the maintenance and differentiation of NPCs and PT cells, as well as their subsequent function.

A-to-I RNA editing in kidney tissue from patients with nephrotic syndrome

Cortical organoids reveal human-specific role of METTL5 in neurodevelopment via regulation of CHCHD2.

Overexpression of CHCHD2 in METTL5-KO NPCs rescued proliferation and partially rescued oxidative metabolism in NPCs and ventricle formation in organoids, highlighting a previously uncharacterized connection between CHCHD2, oxidative metabolism, and METTL5-mediated regulation of human neurogenesis.