Reduced PaxillinB localization to cell-substrate adhesions promotes cell migration in Dictyostelium.

Many cells adhere to extracellular matrix for efficient cell migration. This adhesion is mediated by focal adhesions, a protein complex linking the extracellular matrix to the intracellular cytoskeleton. Focal adhesions have been studied extensively in mesenchymal cells, but recent research in physiological contexts and amoeboid cells suggest focal adhesion regulation differs from the mesenchymal focal adhesion paradigm. We used Dictyostelium discoideum to uncover new mechanisms of focal adhesion regulation, as Dictyostelium are amoeboid cells that form focal adhesion-like structures for migration. We show that PaxillinB, the Dictyostelium homologue of Paxillin, localizes to dynamic focal adhesion-like structures during Dictyostelium migration. Unexpectedly, reduced PaxillinB recruitment to these structures increases Dictyostelium cell migration. Quantitative analysis of focal adhesion size and dynamics show that lack of PaxillinB recruitment to focal adhesions does not alter focal adhesion size, but rather increases focal adhesion turnover. These findings are in direct contrast to Paxillin function at focal adhesions during mesenchymal migration, challenging the established focal adhesion model.

An evolutionary and physiological perspective on cell-substrate adhesion machinery for cell migration.

Cell-substrate adhesion is a critical aspect of many forms of cell migration. Cell adhesion to an extracellular matrix (ECM) generates traction forces necessary for efficient migration. One of the most well-studied structures cells use to adhere to the ECM is focal adhesions, which are composed of a multilayered protein complex physically linking the ECM to the intracellular actin cytoskeleton. Much of our understanding of focal adhesions, however, is primarily derived from in vitro studies in Metazoan systems. Though these studies provide a valuable foundation to the cell-substrate adhesion field, the evolution of cell-substrate adhesion machinery across evolutionary space and the role of focal adhesions in vivo are largely understudied within the field. Furthering investigation in these areas is necessary to bolster our understanding of the role cell-substrate adhesion machinery across Eukaryotes plays during cell migration in physiological contexts such as cancer and pathogenesis. In this review, we review studies of cell-substrate adhesion machinery in organisms evolutionary distant from Metazoa and cover the current understanding and ongoing work on how focal adhesions function in single and collective cell migration in an in vivo environment, with an emphasis on work that directly visualizes cell-substrate adhesions. Finally, we discuss nuances that ought to be considered moving forward and the importance of future investigation in these emerging fields for application in other fields pertinent to adhesion-based processes.

Targeted Next-Generation Sequencing Identifies Pathogenic Variants in Diabetic Kidney Disease.

INTRODUCTION: Diabetes is the most common cause of chronic kidney disease (CKD). For patients with diabetes and CKD, the underlying cause of their kidney disease is often assumed to be a consequence of their diabetes. Without histopathological confirmation, however, the underlying cause of their disease is unclear. Recent studies have shown that next-generation sequencing (NGS) provides a promising avenue toward uncovering and establishing precise genetic diagnoses in various forms of kidney disease. METHODS: Here, we set out to investigate the genetic basis of disease in nondiabetic kidney disease (NDKD) and diabetic kidney disease (DKD) patients by performing targeted NGS using a custom panel comprising 345 kidney disease-related genes. RESULTS: Our analysis identified rare diagnostic variants based on ACMG-AMP guidelines that were consistent with the clinical diagnosis of 19% of the NDKD patients included in this study. Similarly, 22% of DKD patients were found to carry rare pathogenic/likely pathogenic variants in kidney disease-related genes included on our panel. Genetic variants suggestive of NDKD were detected in 3% of the diabetic patients included in this study. DISCUSSION/CONCLUSION: Our findings suggest that rare variants in kidney disease-related genes in a diabetic background may play a role in the pathogenesis of DKD and NDKD in patients with diabetes.