Netrin-1 directs vascular patterning and maturity in the developing kidney.
| Autor: | Honeycutt SE; Department of Cell Biology and Physiology University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., N'Guetta PY; Department of Cell Biology and Physiology University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Hardesty DM; Department of Cell Biology and Physiology University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Xiong Y; Department of Cell Biology and Physiology University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Cooper SL; Department of Cell Biology and Physiology University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., O'Brien LL; Department of Cell Biology and Physiology University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. |
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| Jazyk: | angličtina |
| Zdroj: | BioRxiv : the preprint server for biology [bioRxiv] 2023 Apr 18. Date of Electronic Publication: 2023 Apr 18. |
| DOI: | 10.1101/2023.04.14.536975 |
| Abstrakt: | Blood filtering by the kidney requires the establishment of an intricate vascular system that works to support body fluid and organ homeostasis. Despite these critical roles, little is known about how vascular architecture is established during kidney development. More specifically, how signals from the kidney influence vessel maturity and patterning remains poorly understood. Netrin-1 ( Ntn1 ) is a secreted ligand critical for vessel and neuronal guidance. Here, we demonstrate that Ntn1 is expressed by stromal progenitors in the developing kidney, and conditional deletion of Ntn1 from Foxd1+ stromal progenitors ( Foxd1 GC /+ ; Ntn1 fl/fl ) results in hypoplastic kidneys that display extended nephrogenesis. Despite expression of the netrin-1 receptor Unc5c in the adjacent nephron progenitor niche, Unc5c knockout kidneys develop normally. The netrin-1 receptor Unc5b is expressed by embryonic kidney endothelium and therefore we interrogated the vascular networks of Foxd1 GC /+ ; Ntn1 fl/fl kidneys. Wholemount, 3D analyses revealed the loss of a predictable vascular pattern in mutant kidneys. As vascular patterning has been linked to vessel maturity, we investigated arterialization in these mutants. Quantification of the CD31+ endothelium at E15.5 revealed no differences in metrics such as the number of branches or branch points, whereas the arterial vascular smooth muscle metrics were significantly reduced at both E15.5 and P0. In support of these results, whole kidney RNA-seq showed upregulation of angiogenic programs and downregulation of muscle-related programs which included smooth muscle-associated genes. Together, our findings highlight the significance of netrin-1 to proper vascularization and kidney development. Competing Interests: Competing Interests The authors have nothing to declare and no competing interests, relevant affiliations, financial involvement, or financial conflicts with any entities or organizations that may have financial interests in the research, subject matter, or materials in this manuscript apart from those disclosed. |
| Databáze: | MEDLINE |
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