Unified single-cell analysis of testis gene regulation and pathology in 5 mouse strains
- Washington University School of Medicine, United States
- University of Oxford, United Kingdom
- Oregon Health and Science University, United States
Abstract
To fully exploit the potential of single-cell functional genomics in the study of development and disease, robust methods are needed to simplify the analysis of data across samples, time-points and individuals. Here we introduce a model-based factor analysis method, SDA, to analyse a novel 57,600-cell dataset from the testes of wild-type mice and mice with gonadal defects due to disruption of the genes Mlh3, Hormad1, Cul4a or Cnp. By jointly analysing mutant and wild-type cells we decomposed our data into 46 components that identify novel meiotic gene-regulatory programmes, mutant-specific pathological processes, and technical effects, and provide a framework for imputation. We identify, de novo, DNA sequence motifs associated with individual components that define temporally varying modes of gene expression control. Analysis of SDA components also led us to identify a rare population of macrophages within the seminiferous tubules of Mlh3-/- and Hormad1-/- mice, an area typically associated with immune privilege.
Data availability
Raw data and processed files for Drop-seq and 10X Genomics experiments are available in GEO under accession number: GSE113293
-
A single-cell atlas of testis gene expression from 5 mouse strainsNCBI Gene Expression Omnibus, GSE113293.
-
Novel Insights into the Downstream Pathways and Targets Controlled by Transcription Factors CREM in the TestisPLoS One, doi:10.1371/journal.pone.0031798.s009.
-
RFX2 Is a Major Transcriptional Regulator of Spermiogenesis.PLoS Genetics, doi:10.1371/journal.pgen.1005368.s011.
Article and author information
Author details
Funding
Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD078641)
- Donald F Conrad
National Institute of Mental Health (R01MH101810)
- Donald F Conrad
Wellcome (098387/Z/12/Z)
- Simon R Myers
Wellcome (109109/Z/15/Z)
- Daniel Wells
European Research Council (617306)
- Jonathan Marchini
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 performed in compliance with the regulations of the Animal Studies Committee at Washington University in St. Louis under approved protocol #20160089.
Reviewing Editor
- Deborah Bourc'his, Institut Curie, France
Version history
- Received: November 28, 2018
- Accepted: June 17, 2019
- Accepted Manuscript published: June 25, 2019 (version 1)
- Version of Record published: July 9, 2019 (version 2)
Copyright
© 2019, Jung 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
-
- 8,577
- Page views
-
- 867
- Downloads
-
- 61
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
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)
Unified single-cell analysis of testis gene regulation and pathology in 5 mouse strains
eLife 8:e43966.
https://doi.org/10.7554/eLife.43966
Further reading
-
- Computational and Systems Biology
- Neuroscience
The cerebellar granule cell layer has inspired numerous theoretical models of neural representations that support learned behaviors, beginning with the work of Marr and Albus. In these models, granule cells form a sparse, combinatorial encoding of diverse sensorimotor inputs. Such sparse representations are optimal for learning to discriminate random stimuli. However, recent observations of dense, low-dimensional activity across granule cells have called into question the role of sparse coding in these neurons. Here, we generalize theories of cerebellar learning to determine the optimal granule cell representation for tasks beyond random stimulus discrimination, including continuous input-output transformations as required for smooth motor control. We show that for such tasks, the optimal granule cell representation is substantially denser than predicted by classical theories. Our results provide a general theory of learning in cerebellum-like systems and suggest that optimal cerebellar representations are task-dependent.
-
- Computational and Systems Biology
- Neuroscience
Previous research has highlighted the role of glutamate and gamma-aminobutyric acid (GABA) in perceptual, cognitive, and motor tasks. However, the exact involvement of these neurochemical mechanisms in the chain of information processing, and across human development, is unclear. In a cross-sectional longitudinal design, we used a computational approach to dissociate cognitive, decision, and visuomotor processing in 293 individuals spanning early childhood to adulthood. We found that glutamate and GABA within the intraparietal sulcus (IPS) explained unique variance in visuomotor processing, with higher glutamate predicting poorer visuomotor processing in younger participants but better visuomotor processing in mature participants, while GABA showed the opposite pattern. These findings, which were neurochemically, neuroanatomically and functionally specific, were replicated ~21 mo later and were generalized in two further different behavioral tasks. Using resting functional MRI, we revealed that the relationship between IPS neurochemicals and visuomotor processing is mediated by functional connectivity in the visuomotor network. We then extended our findings to high-level cognitive behavior by predicting fluid intelligence performance. We present evidence that fluid intelligence performance is explained by IPS GABA and glutamate and is mediated by visuomotor processing. However, this evidence was obtained using an uncorrected alpha and needs to be replicated in future studies. These results provide an integrative biological and psychological mechanistic explanation that links cognitive processes and neurotransmitters across human development and establishes their potential involvement in intelligent behavior.
