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Sexually Dimorphic Gene Expression in the Mammalian Brain
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In recent times, major advances have been made towards understanding sexual dimorphism in the brain on a molecular basis. This thesis summarises my modest contributions to these endeavours. Sexual dimorphisms are manifested throughout the spectrum of biological complexity, and can be studied by numerous approaches. The approach of this thesis is to explore sex-biased gene expression in mammalian somatic tissues. Paper I describes an evolutionarily conserved sexual gene expression pattern in the primate brain. Conserved sex-biased genes may underlie important sex differences in neurobiology. In Paper II, Y-chromosome genes expressed across several regions of the human male brain during mid-gestation are identified. Such genes may play male-specific roles during brain development. The studies of Papers III and IV explore sex-biased gene expression in several somatic tissues from mouse. The amount of genes with sex-biased expression varied in different brain regions. The striatum was particularly interesting, with an order of magnitude increase in the number of sex-biased genes as compared to the other included brain regions. Of potentially wider significance are my observations regarding the transcriptional regulation of domains that escape X-chromosome inactivation (XCI). Specifically, I provide the first evidence that long non-coding RNAs (lncRNAs) transcribe together with protein-coding genes in XCI-escaping domains. This raises the possibility that lncRNAs mediate the transcriptional regulation of XCI-escaping domains. I also present evidence that the mouse X-chromosome has undergone both feminisation and de-masculinisation during evolution, as indicated by the sex-skewed regulation of genes on this chromosome. This finding is relevant for understanding the selective forces that shaped the mammalian X-chromosome. In the final chapter, Paper V, the generation of a novel transgenic mouse line, Gpr101-Cre, is described. Its progeny can be used for functional studies of striatum, a brain structure with major sexual dimorphism, as is further demonstrated in the Papers of this thesis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2011. , p. 57
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 840
National Category
Developmental Biology
Identifiers
URN: urn:nbn:se:uu:diva-156640ISBN: 978-91-554-8118-6 (print)OAI: oai:DiVA.org:uu-156640DiVA, id: diva2:432663
Public defence
2011-09-16, Zootissalen (EBC 01.01006), Evolutionsbiologiskt centrum, EBC, Norbyvägen, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2011-08-26 Created: 2011-08-04 Last updated: 2011-11-10
List of papers
1. Prenatal sex differences in the human brain
Open this publication in new window or tab >>Prenatal sex differences in the human brain
2009 (English)In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 14, no 11, p. 988-989Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
London, UK: Nature Publishing Group, 2009
Keyword
sex, brain, gene expression, sex differences, sexual dimorphism, human, Y, Y chromosome, Y-chromosome
National Category
Developmental Biology
Research subject
Genetics
Identifiers
urn:nbn:se:uu:diva-112066 (URN)10.1038/mp.2009.79 (DOI)000271022100001 ()
Available from: 2010-01-08 Created: 2010-01-08 Last updated: 2017-12-12Bibliographically approved
2. mRNA expression of Y-linked transcripts in 12 regions of the prenatal human male brain (Featured Image)
Open this publication in new window or tab >>mRNA expression of Y-linked transcripts in 12 regions of the prenatal human male brain (Featured Image)
2009 (English)In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 14, no 11, p. 987-Article in journal (Refereed) Published
Place, publisher, year, edition, pages
London, UK: Nature Publishing Group, 2009
National Category
Developmental Biology
Research subject
Genetics
Identifiers
urn:nbn:se:uu:diva-112069 (URN)10.1038/mp.2009.114 (DOI)
Note
Featured ImageAvailable from: 2010-01-08 Created: 2010-01-08 Last updated: 2017-12-12Bibliographically approved
3. A new mouse line based on the Gpr101 promoter drives expression of Cre in medium spiny neurons of the striatum.
Open this publication in new window or tab >>A new mouse line based on the Gpr101 promoter drives expression of Cre in medium spiny neurons of the striatum.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

A novel transgenic mouse that expresses the Cre recombinase in striatal medium spiny neurons was generated. To create the line, we have used the promoter of the X-linked gene Gpr101 and a Bacterial Artificial Chromosome recombineering strategy. When the Gpr101-Cre mouse was bred to the tdTomato Ai14 [1] reporter line, we observed strong fluorescence in medium-size spiny neurons (MSNs) of the striatum. In addition, Gpr101-Cre was detected in hippocampal pyramidal neurons and sparse cerebellar purkinje cells. Interestingly, Gpr101-Cre expression in this mouse line differs from the endogenous Gpr101 gene expression, which is highest in amygdala and hypothalamus and not detected in striatum in adult mice, as shown by in situ hybridization. The tdTomato Ai14 reporter marks any cell lineages in which Gpr101-Cre has, at any time, been expressed. Our results show that the Gpr101-Cre gene construct had lost the original ability of the Gpr101 promotor to drive expression of the Gpr101 gene in the amygdala and the hypothalamus. Second, the Gpr101-Cre gene construct either acquired a novel capability to express in striatum, or more probably, Gpr101 is expressed transiently in striatum during development. In addition, a small subpopulation of astrocytes (GFAP positive cells) was labelled in several regions of the central nervous system, allowing for specific follow-up studies of these cells. We envision that the newly created Cre-line will contribute to numerous studies, particularly related to the development and differentiation of cellular networks in the brain.

Identifiers
urn:nbn:se:uu:diva-156638 (URN)
Available from: 2011-08-04 Created: 2011-08-04 Last updated: 2012-02-24
4. Large-scale sex-bias expression analysis of somatic tissues reveals de-masculinisation of the mouse X-chromosome.
Open this publication in new window or tab >>Large-scale sex-bias expression analysis of somatic tissues reveals de-masculinisation of the mouse X-chromosome.
Show others...
(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:uu:diva-156639 (URN)
Available from: 2011-08-04 Created: 2011-08-04 Last updated: 2011-08-26
5. An evolutionarily conserved sexual signature in the primate brain
Open this publication in new window or tab >>An evolutionarily conserved sexual signature in the primate brain
Show others...
2008 (English)In: PLoS Genetics, ISSN 1553-7390, Vol. 4, no e1000100Article in journal (Refereed) Published
Abstract [en]

The question of a potential biological sexual signature in the human brain is a heavily disputed subject. In order to provide further insight into this issue, we used an evolutionary approach to identify genes with sex differences in brain expression level among primates. We reasoned that expression patterns important to uphold key male and female characteristics may be conserved during evolution. We selected cortex for our studies because this specific brain region is responsible for many higher behavioral functions. We compared gene expression profiles in the occipital cortex of male and female humans (Homo sapiens, a great ape) and cynomolgus macaques (Macaca fascicularis, an old world monkey), two catarrhine species that show abundant morphological sexual dimorphism, as well as in common marmosets ( Callithrix Jacchus, a new world monkey) which are relatively sexually monomorphic. We identified hundreds of genes with sex-biased expression patterns in humans and macaques, while fewer than ten were differentially expressed between the sexes in marmosets. In primates, a general rule is that many of the morphological and behavioral sexual dimorphisms seen in polygamous species, such as macaques, are typically less pronounced in monogamous species such as the marmosets. Our observations suggest that this correlation may also be reflected in the extent of sex-biased gene expression in the brain. We identified 85 genes with common sex-biased expression, in both human and macaque and 2 genes, X inactivation-specific transcript (XIST) and Heat shock factor binding protein 1 ( HSBP1), that were consistently sex-biased in the female direction in human, macaque, and marmoset. These observations imply a conserved signature of sexual gene expression dimorphism in cortex of primates. Further, we found that the coding region of female-biased genes is more evolutionarily constrained compared to the coding region of both male-biased and non sex-biased brain expressed genes. We found genes with conserved sexual gene expression dimorphism in the occipital cortex of humans, cynomolgus macaques, and common marmosets. Genes within sexual expression profiles may underlie important functional differences between the sexes, with possible importance during primate evolution.

National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-106379 (URN)10.1371/journal.pgen.1000100 (DOI)000260410300014 ()
Available from: 2009-06-22 Created: 2009-06-22 Last updated: 2016-04-25Bibliographically approved
6. Female-biased expression of long non-coding RNAs in domains that escape X-inactivation in mouse
Open this publication in new window or tab >>Female-biased expression of long non-coding RNAs in domains that escape X-inactivation in mouse
Show others...
2010 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 11, no 1, p. 614-Article in journal (Refereed) Published
Abstract [en]

Background:

Sexual dimorphism in brain gene expression has been recognized in several animal species.However, the relevant regulatory mechanisms remain poorly understood. To investigatewhether sex-biased gene expression in mammalian brain is globally regulated or locallyregulated in diverse brain structures, and to study the genomic organisation of brain-expressedsex-biased genes, we performed a large scale gene expression analysis of distinct brainregions in adult male and female mice.

Results:

This study revealed spatial specificity in sex-biased transcription in the mouse brain, andidentified 173 sex-biased genes in the striatum; 19 in the neocortex; 12 in the hippocampusand 31 in the eye. Genes located on sex chromosomes were consistently over-represented inall brain regions. Analysis on a subset of genes with sex-bias in more than one tissue revealedY-encoded male-biased transcripts and X-encoded female-biased transcripts known to escapeX-inactivation. In addition, we identified novel coding and non-coding X-linked genes withfemale-biased expression in multiple tissues. Interestingly, the chromosomal positions of allof the female-biased non-coding genes are in close proximity to protein-coding genes thatescape X-inactivation. This defines X-chromosome domains each of which contains a codingand a non-coding female-biased gene. Lack of repressive chromatin marks in non-codingtranscribed loci supports the possibility that they escape X-inactivation. Moreover, RNADNAcombined FISH experiments confirmed the biallelic expression of one such noveldomain.

Conclusion:

This study demonstrated that the amount of genes with sex-biased expression variesbetween individual brain regions in mouse. The sex-biased genes identified are localized onmany chromosomes. At the same time, sexually dimorphic gene expression that is common toseveral parts of the brain is mostly restricted to the sex chromosomes. Moreover, the studyuncovered multiple female-biased non-coding genes that are non-randomly co-localized onthe X-chromosome with protein-coding genes that escape X-inactivation. This raises thepossibility that expression of long non-coding RNAs may play a role in modulating geneexpression in domains that escape X-inactivation in mouse.

Keyword
long non-coding RNA, X-inactivation, female-biased, sex-biased, gene, gene expression, lncRNA, noncoding RNA, X-chromosome, brain, sex, hippocampus, neocortex, striatum, eye, lung, escape X-inactivation, domains
National Category
Medical and Health Sciences Biological Sciences
Research subject
Genetics; Biology with specialization in Animal Development; Neuroscience
Identifiers
urn:nbn:se:uu:diva-133284 (URN)10.1186/1471-2164-11-614 (DOI)000284579400001 ()21047393 (PubMedID)
Available from: 2010-11-05 Created: 2010-11-05 Last updated: 2017-12-12Bibliographically approved

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