Nephron progenitor commitment is a stochastic process influenced by cell migration
Abstract
Progenitor self-renewal and differentiation is often regulated by spatially restricted cues within a tissue microenvironment. Here we examine how progenitor cell migration impacts regionally induced commitment within the nephrogenic niche in mice. We identify a subset of cells that express Wnt4, an early marker of nephron commitment, but migrate back into the progenitor population where they accumulate over time. Single cell RNA-seq and computational modelling of returning cells reveals that nephron progenitors can traverse the transcriptional hierarchy between self-renewal and commitment in either direction. This plasticity may enable robust regulation of nephrogenesis as niches remodel and grow during organogenesis.
Data availability
Single cell sequencing data has been deposited in GEO under accession code GSE118486. Gene lists from the single cell analysis and code for the simulation of cell migration and stochastic commitment have been provided as Supplementary Files.
Article and author information
Author details
Funding
National Health and Medical Research Council (GNT1156567)
- Alexander Nicholas Combes
Australian Research Council (DE150100652)
- Alexander Nicholas Combes
Murdoch Children's Research Institute
- Alexander Nicholas Combes
National Health and Medical Research Council (GNT1136085)
- Melissa H Little
National Health and Medical Research Council (GNT1063989)
- Melissa H Little
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments were assessed and approved by the Murdoch Children's Research Institute Animal Ethics Committee (A783/A894) and were conducted in accordance with applicable Australian laws governing the care and use of animals for scientific purposes.
Copyright
© 2019, Lawlor et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Further reading
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- Cell Biology
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Long thought to have little relevance to ovarian physiology, the rete ovarii may have a role in follicular dynamics and reproductive health.
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- Cell Biology
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The rete ovarii (RO) is an appendage of the ovary that has been given little attention. Although the RO appears in drawings of the ovary in early versions of Gray’s Anatomy, it disappeared from recent textbooks, and is often dismissed as a functionless vestige in the adult ovary. Using PAX8 immunostaining and confocal microscopy, we characterized the fetal development of the RO in the context of the mouse ovary. The RO consists of three distinct regions that persist in adult life, the intraovarian rete (IOR), the extraovarian rete (EOR), and the connecting rete (CR). While the cells of the IOR appear to form solid cords within the ovary, the EOR rapidly develops into a convoluted tubular epithelium ending in a distal dilated tip. Cells of the EOR are ciliated and exhibit cellular trafficking capabilities. The CR, connecting the EOR to the IOR, gradually acquires tubular epithelial characteristics by birth. Using microinjections into the distal dilated tip of the EOR, we found that luminal contents flow toward the ovary. Mass spectrometry revealed that the EOR lumen contains secreted proteins potentially important for ovarian function. We show that the cells of the EOR are closely associated with vasculature and macrophages, and are contacted by neuronal projections, consistent with a role as a sensory appendage of the ovary. The direct proximity of the RO to the ovary and its integration with the extraovarian landscape suggest that it plays an important role in ovary development and homeostasis.