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Spatial sexual dimorphism of X and Y homolog gene expression in the human central nervous system during early male development
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).ORCID iD: 0000-0001-7509-8071
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Number of Authors: 92016 (English)In: Biology of Sex Differences, ISSN 2042-6410, Vol. 7Article in journal (Refereed) Published
Abstract [en]

Background: Renewed attention has been directed to the functions of the Y chromosome in the central nervous system during early human male development, due to the recent proposed involvement in neurodevelopmental diseases. PCDH11Y and NLGN4Y are of special interest because they belong to gene families involved in cell fate determination and formation of dendrites and axon. Methods: We used RNA sequencing, immunocytochemistry and a padlock probing and rolling circle amplification strategy, to distinguish the expression of X and Y homologs in situ in the human brain for the first time. To minimize influence of androgens on the sex differences in the brain, we focused our investigation to human embryos at 8-11 weeks post-gestation. Results: We found that the X- and Y-encoded genes are expressed in specific and heterogeneous cellular sub-populations of both glial and neuronal origins. More importantly, we found differential distribution patterns of X and Y homologs in the male developing central nervous system. Conclusions: This study has visualized the spatial distribution of PCDH11X/Y and NLGN4X/Y in human developing nervous tissue. The observed spatial distribution patterns suggest the existence of an additional layer of complexity in the development of the male CNS.

Place, publisher, year, edition, pages
2016. Vol. 7
Keywords [en]
Sex differences, Human embryo development, Female, Male, Gene expression, Protocadherin, Neuroligin, X chromosome, Y chromosome, Brain, Spinal cord, Cortex, Medulla oblongata, Rolling circle amplification, PCDH11X, PCDH11Y, NLGN4X, NLGN4Y, ISLET1, OLIG2, SOX10, NeuN
National Category
Biological Sciences Medical Genetics
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:su:diva-126904DOI: 10.1186/s13293-015-0056-4ISI: 000368237900003PubMedID: 26759715OAI: oai:DiVA.org:su-126904DiVA, id: diva2:903887
Available from: 2016-02-17 Created: 2016-02-16 Last updated: 2020-03-05Bibliographically approved
In thesis
1. RNA-based spatial characterization of cell and tissue heterogeneity
Open this publication in new window or tab >>RNA-based spatial characterization of cell and tissue heterogeneity
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Technical advances in cell biology have revolutionized the field of cell biology. With new technology it is now possible to address scientific questions in cell biology at the molecular level. Single-cell RNA-sequencing can reveal transcriptomic information for single cells and spatially resolved transcriptomic technology can visualize thousands or millions of cells and transcripts for spatial molecular profiling. The work in this thesis describes the technological development from traditional in situ hybridization to the current state-of-the-art technology for spatial multiplexed gene expression analysis. This development has enabled RNA-based molecular characterization of cells and tissues with the spatial dimension maintained. The work included in the thesis highlights the potential and the advantages of padlock-probe-based technology for spatial RNA-based profiling of cells and tissues. Furthermore, it demonstrates the possibilities arising from the inherent ability of padlock probes to distinguish between transcripts based on differences in single nucleotides.

The study in paper I investigates the prevalence of Enterovirus species B in patients with Crohn’s disease by a chromogenic in situ hybridization assay combined with immunohistochemistry to detect viral RNA and proteins directly in tissue samples.

In paper II, padlock probes were used to study the spatial gene expression of gene homologs from the X and Y chromosome in human embryonic nervous tissue. Furthermore, a strategy was devised to visualize and evaluate spatial expression patterns.

The padlock probe-based approach for multiplexed spatial transcriptional profiling, in situ sequencing, was applied in paper III to study the regional and cell-type-specific dynamics of A-to-I RNA editing in the developing mouse brain.

In paper IV, a technical characterization of padlock probes was performed with the aim of determining how to design a padlock probe to obtain optimal detection efficiency.

The work in this thesis demonstrates the dramatic shift in how biological questions in cell and tissue biology can be addressed, enabled by the technological evolution of traditional in situ hybridization assays into high-throughput, multiplexed spatial transcription profiling.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2020. p. 65
Keywords
Padlock probes, in situ sequencing, single cell resolution, single nucleotide variant resolution, spatial transcription profiling
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-177114 (URN)978-91-7797-958-6 (ISBN)978-91-7797-959-3 (ISBN)
Public defence
2020-02-14, Air & Fire, Science for Life Laboratory, Tomtebodavägen 23 A, Solna, 10:00 (English)
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Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript.

Available from: 2020-01-22 Created: 2019-12-17 Last updated: 2020-05-25Bibliographically approved

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