Abstract: FR-PO919
Netrin-1 Directs Neurovascular Patterning Required for Proper Kidney Development
Session Information
- Development, Stem Cells, Regenerative Medicine - II
October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Development, Stem Cells, and Regenerative Medicine
- 501 Development, Stem Cells, and Regenerative Medicine: Basic
Authors
- O'Brien, Lori L., University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
- Hardesty, Deanna Marie, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
- Cooper, Shamus Luke, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
Background
Proper kidney development requires the coordinated growth and differentiation of multiple cell types. Alterations to nephron number and function can have significant health consequences. While advances have been made in elucidating how nephron progenitors form, differentiate, and interact with the adjacent stroma and collecting duct system, almost nothing is known about how the neural and vascular systems influence these processes or even how they become established in the fetal kidney. This is a significant void in our understanding, given the critical importance of vascular perfusion and innervation for mature organ formation and function.
Methods
To this end, we have interrogated the function of netrin-1 in the developing kidney. Netrin-1 is an axon guidance cue which also regulates vessel pathfinding. Netrin-1 (Ntn1) is highly expressed by the stromal progenitors. We conditionally deleted Ntn1 in these cells and examined the resulting phenotypes with light-sheet and confocal microscopy in addition to standard histological techniques.
Results
Ntn1 loss results in abbarent neural and vascular networks. Normal patterning is disrupted, leading to localized networks which are in excess or deficient. Additionally, ectopic neurovascular tracts are found on the outside surface of the kidney which can infiltrate and severely disrupt local tissue morphology. Mutant kidneys are hypoplastic with an extension of nephron progenitor lifespan by ~2 days. Deletion of Unc5c, a known receptor for netrin-1 which is expressed by the nephron progenitors, does not result in any obvious developmental defects. Therefore, we predict the hypoplastic and progenitor phenotypes we observe are due to a disruption in signals that the nerves/vessels supply to nephron progenitors and the branching collecting duct system, rather than a direct action of netrin-1. Consistent with congenital renal defects having ongoing effects into adulthood, we find that mutant adult kidneys show focally dilated and vacuolated tubules indicative of tubular injury, as well as abnormal glomerular histology.
Conclusion
These studies have provided novel insights into the establishment of neurovascular networks in the developing kidney and the implications for adult function. Such findings will help inform efforts to engineer kidneys de novo, where establishing proper kidney filtration will be essential.