Julio Fierro Morales

All Publications

• Differential PaxillinB dynamics at Dictyostelium cell-substrate adhesions. Biology open Fierro Morales, J. C., Roh-Johnson, M. 2025; 14 (10)

  Abstract

  Adhesion-based migration is regulated by focal adhesions: multi-protein nanostructures linking the intracellular cytoskeleton to the extracellular substrate. Efficient adhesion-based migration has been shown to be regulated by focal adhesion dynamics such as lifetime, size and turnover, which in turn are influenced by the molecular composition of focal adhesions. We recently identified the formation of cell-substrate adhesion populations in Dictyostelium discoideum with differing molecular compositions, but it is unclear how these distinct compositions influence Dictyostelium adhesion dynamics and cell migration. Here, we further investigate the role of VinculinB - the Dictyostelium homologue of Vinculin - localization on Dictyostelium adhesion lifetime and protein turnover during cell migration. We show that co-localization of VinculinB to PaxillinB-positive cell-substrate adhesions increases adhesion lifetime without changing PaxillinB turnover. We further show that truncation of the PaxillinB N-terminus, which perturbs VinculinB co-localization to adhesions, surprisingly also increases adhesion lifetime and decreases PaxillinB turnover at adhesions. These findings suggest that similar to mammalian focal adhesions, molecular composition of Dictyostelium cell-substrate adhesion regulates their adhesion lifetimes and protein turnover, providing insight into how cell-substrate adhesions function during Dictyostelium cell migration.

  View details for DOI 10.1242/bio.062197

  View details for PubMedID 40931968

  View details for PubMedCentralID PMC12505270

• Reduced cell-substrate adhesion formation promotes cell migration in Dictyostelium. Molecular biology of the cell Fierro Morales, J. C., A Nguyen, T., Nepal, S., Redfearn, C., Gale, B. K., Titus, M. A., Roh-Johnson, M. 2025; 36 (8): ar98

  Abstract

  Many cells adhere to the extracellular matrix (ECM) for efficient cell migration. This adhesion is mediated by focal adhesions, a protein complex linking the ECM to the intracellular cytoskeleton. Focal adhesions have been studied extensively in metazoan mesenchymal cells, but recent research in physiological contexts and amoeboid cells suggests that focal adhesion regulation differs from the mesenchymal focal adhesion paradigm. Although focal adhesion machinery predates the origin of metazoans, focal adhesion formation and regulation during nonmetazoan cell migration is largely unexplored. We used Dictyostelium discoideum to investigate potential novel mechanisms and the evolution of focal adhesion regulation, as Dictyostelium are nonmetazoans that form cell-substrate adhesion structures for migration. We show that PaxillinB, the Dictyostelium homologue of Paxillin, localizes to dynamic cell-substrate adhesions. As expected, PaxillinB mutations decreased the number of cell-substrate adhesions. Unexpectedly, however, decreased cell-substrate adhesion number led to an increase in cell migration speed. These findings are in direct contrast to Paxillin function at focal adhesions and regulation of cell migration in mammalian cells, challenging the established focal adhesion model and providing insight into the evolution of cell-substrate adhesions and Paxillin function during cell migration.

  View details for DOI 10.1091/mbc.E25-05-0230

  View details for PubMedID 40498666

  View details for PubMedCentralID PMC12367306

• An evolutionary and physiological perspective on cell-substrate adhesion machinery for cell migration. Frontiers in cell and developmental biology Fierro Morales, J. C., Xue, Q., Roh-Johnson, M. 2022; 10: 943606

  Abstract

  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.

  View details for DOI 10.3389/fcell.2022.943606

  View details for PubMedID 36092727

  View details for PubMedCentralID PMC9453864

• A dominant negative ADIPOQ mutation in a diabetic family with renal disease, hypoadiponectinemia, and hyperceramidemia. NPJ genomic medicine Simeone, C. A., Wilkerson, J. L., Poss, A. M., Banks, J. A., Varre, J. V., Guevara, J. L., Hernandez, E. J., Gorsi, B., Atkinson, D. L., Turapov, T., Frodsham, S. G., Morales, J. C., O'Neil, K., Moore, B., Yandell, M., Summers, S. A., Krolewski, A. S., Holland, W. L., Pezzolesi, M. G. 2022; 7 (1): 43

  Abstract

  Adiponectin, encoded by ADIPOQ, is an insulin-sensitizing, anti-inflammatory, and renoprotective adipokine that activates receptors with intrinsic ceramidase activity. We identified a family harboring a 10-nucleotide deletion mutation in ADIPOQ that cosegregates with diabetes and end-stage renal disease. This mutation introduces a frameshift in exon 3, resulting in a premature termination codon that disrupts translation of adiponectin's globular domain. Subjects with the mutation had dramatically reduced circulating adiponectin and increased long-chain ceramides levels. Functional studies suggest that the mutated protein acts as a dominant negative through its interaction with non-mutated adiponectin, decreasing circulating adiponectin levels, and correlating with metabolic disease.

  View details for DOI 10.1038/s41525-022-00314-z

  View details for PubMedID 35869090

  View details for PubMedCentralID PMC9307825

• Targeted Next-Generation Sequencing Identifies Pathogenic Variants in Diabetic Kidney Disease. American journal of nephrology Lazaro-Guevara, J., Fierro-Morales, J., Wright, A. H., Gunville, R., Simeone, C., Frodsham, S. G., Pezzolesi, M. H., Zaffino, C. A., Al-Rabadi, L., Ramkumar, N., Pezzolesi, M. G. 2021; 52 (3): 239-249

  Abstract

  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.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.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.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.

  View details for DOI 10.1159/000514578

  View details for PubMedID 33774617

  View details for PubMedCentralID PMC8653779