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Kidney Week

Abstract: FR-PO930

Homeogene Emx1 Is a Required Downstream Component of the Mecom-Tbx2 Genetic Pathway That Regulates Pronephros Distal Segment Formation

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 501 Development, Stem Cells, and Regenerative Medicine: Basic

Authors

  • Morales, Elvin e, University of Notre Dame, Notre Dame, Indiana, United States
  • Wingert, Rebecca A., University of Notre Dame, Notre Dame, Indiana, United States
Background

Vertebrate kidneys contain nephron functional units where specialized cell types are organized into segments with discrete physiological roles. Many gaps remain in our understanding of how segment regions develop. To date, several studies have identified key signaling molecules and transcription factors that are essential for segment patterning in the pronephros, which has been speculated to offer a primitive blueprint for nephron segmentation in other kidney forms. empty spiracles homeobox gene 1 (emx1) encodes a homeodomain transcription factor that is expressed in renal progenitors during early stages of pronephros development, and numbers among those genes that have been implicated to act downstream of retinoic acid (RA) signaling during segmentation.

Methods

Here, we used reverse genetics approaches to study the role of emx1 during nephron formation. We discovered that emx1 is required to regulate the balance of distal segment domains within the distal pronephros, and then performed a suite of genetic epistasis and expression studies to elucidate its relationship with other essential segment patterning components.

Results

emx1 deficiency altered distal segment domains without changes in cell turnover or physical traits like cell size and morphology. In exploring further how Emx1 influences nephron pattern, we found that RA, which induces proximal and represses distal fates during early intermediate mesoderm development, negatively regulates emx1 expression. Next, through a series of epistasis studies, we found that Emx1 acts downstream of a genetic cascade involving the essential distal segment genes Mecom and Tbx2. Finally, we determined that Emx1 restricts the expression boundary of irx3b to control distal segment territories.

Conclusion

Taken together, our work reveals how emx1 is a necessary component of the pronephros genetic segmentation network, which has broad implications for understanding the regulatory cascades that orchestrate vertebrate nephron patterning.

Funding

  • NIDDK Support