RUNX1 marks a luminal castration resistant lineage established at the onset of prostate development
- Cancer Research UK Manchester Institute, The University of Manchester, United Kingdom
- Cancer Research UK Beatson Institute, United Kingdom
- The Christie NHS Foundation Trust, United Kingdom
Abstract
The characterization of prostate epithelial hierarchy and lineage heterogeneity is critical to understand its regenerative properties and malignancies. Here, we report that the transcription factor RUNX1 marks a specific subpopulation of proximal luminal cells (PLCs), enriched in the periurethral region of the developing and adult mouse prostate, and distinct from the previously identified NKX3.1+ luminal castration resistant cells. Using scRNA-seq profiling and genetic lineage tracing, we show that RUNX1+ PLCs are unaffected by androgen deprivation, and do not contribute to the regeneration of the distal luminal compartments. Furthermore, we demonstrate that a transcriptionally similar RUNX1+ population emerges at the onset of embryonic prostate specification to populate the proximal region of the ducts. Collectively, our results reveal that RUNX1+ PLCs is an intrinsic castration-resistant and self-sustained lineage that emerges early during prostate development and provide new insights into the lineage relationships of the prostate epithelium.
Data availability
Raw sequencing files and processed gene expression matrices have been deposited in the NCBI Gene Expression Omnibus under the accession number GSE151944. The processed datasets for both mouse adult prostate and UGS prostate explant cultures can be accessed via a searchable R Shiny application available at http://shiny.cruk.manchester.ac.uk/pscapp/. All code used to process data and generate figures is available on a public GitHub repository at https://github.com/glacaud/prostate-scRNAseq.
-
Runx1 marks a luminal castration resistant lineage established at the onset of prostate developmentNCBI Gene Expression Omnibus, GSE151944.
Article and author information
Author details
Funding
Cancer Research UK (C5759/A20971)
- Esther Baena
- Georges Lacaud
Cancer Research UK (C596/A17196)
- Karen Blyth
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal experiments were approved by the Animal Welfare and Ethics Review Body (AWERB) of the Cancer Research UK Manchester Institute and conducted according to the UK Home Office Project Licence (PPL 70/8580). Genetic lineage-tracing experiments were performed at the Beatson Biological Services Unit (PPL 70/8645 & P5EE22AEE) and approved by the University of Glasgow AWERB. Mice were maintained in purpose-built facility in a 12-hour light/dark cycle with continual access to food and water. All animal procedures were performed on adult males at least 7 weeks of age. Surgical castration was carried out under aseptic conditions.
Copyright
© 2020, Mevel 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.
Metrics
-
- 2,406
- views
-
- 268
- downloads
-
- 33
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
RUNX1 marks a luminal castration resistant lineage established at the onset of prostate development
eLife 9:e60225.
https://doi.org/10.7554/eLife.60225
Further reading
-
- Developmental Biology
The morphogen FGF8 establishes graded positional cues imparting regional cellular responses via modulation of early target genes. The roles of FGF signaling and its effector genes remain poorly characterized in human experimental models mimicking early fetal telencephalic development. We used hiPSC-derived cerebral organoids as an in vitro platform to investigate the effect of FGF8 signaling on neural identity and differentiation. We found that FGF8 treatment increases cellular heterogeneity, leading to distinct telencephalic and mesencephalic-like domains that co-develop in multi-regional organoids. Within telencephalic regions, FGF8 affects the anteroposterior and dorsoventral identity of neural progenitors and the balance between GABAergic and glutamatergic neurons, thus impacting spontaneous neuronal network activity. Moreover, FGF8 efficiently modulates key regulators responsible for several human neurodevelopmental disorders. Overall, our results show that FGF8 signaling is directly involved in both regional patterning and cellular diversity in human cerebral organoids and in modulating genes associated with normal and pathological neural development.
-
- Developmental Biology
Wnt signaling plays crucial roles in embryonic patterning including the regulation of convergent extension (CE) during gastrulation, the establishment of the dorsal axis, and later, craniofacial morphogenesis. Further, Wnt signaling is a crucial regulator of craniofacial morphogenesis. The adapter proteins Dact1 and Dact2 modulate the Wnt signaling pathway through binding to Disheveled. However, the distinct relative functions of Dact1 and Dact2 during embryogenesis remain unclear. We found that dact1 and dact2 genes have dynamic spatiotemporal expression domains that are reciprocal to one another suggesting distinct functions during zebrafish embryogenesis. Both dact1 and dact2 contribute to axis extension, with compound mutants exhibiting a similar CE defect and craniofacial phenotype to the wnt11f2 mutant. Utilizing single-cell RNAseq and an established noncanonical Wnt pathway mutant with a shortened axis (gpc4), we identified dact1/2-specific roles during early development. Comparative whole transcriptome analysis between wildtype and gpc4 and wildtype and dact1/2 compound mutants revealed a novel role for dact1/2 in regulating the mRNA expression of the classical calpain capn8. Overexpression of capn8 phenocopies dact1/2 craniofacial dysmorphology. These results identify a previously unappreciated role of capn8 and calcium-dependent proteolysis during embryogenesis. Taken together, our findings highlight the distinct and overlapping roles of dact1 and dact2 in embryonic craniofacial development, providing new insights into the multifaceted regulation of Wnt signaling.
