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Cellular sexual dimorphism of X and Y homolog gene expression in human central nervous system during early male development
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology. (Jazin)
(English)Manuscript (preprint) (Other academic)
Abstract [en]

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 axons. 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 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. The most striking result was that the Y encoded genes are expressed in specific and heterogeneous cellular neural subpopulations that rarely express the X homologs. Our findings suggest that a male-specific cellular network may exist in the embryonic central nervous system.

Keyword [sv]
y chromosome, PCDH11Y, PCDH11X, NLGN4Y, NLGN4Y, spinal cord, medulla oblongata, fetal, embryo, early development, 8 week pcw, male, female, sex differences, expression, cellular, cellular networks, male specific, male specific cellular networks, neun, actb, sox10, olig2, white matter, eppendymal layer, olivary nucleus, padlock, padlock probing, in situ hybridization, rolling circle amplification
National Category
Neurosciences Developmental Biology
Research subject
Biology with specialization in Molecular Biology; Neurology; Biology with specialization in Evolutionary Organismal Biology
Identifiers
URN: urn:nbn:se:uu:diva-261683OAI: oai:DiVA.org:uu-261683DiVA: diva2:850940
Funder
Swedish Research Council, K2012-61X-22089-01-3
Available from: 2015-09-02 Created: 2015-09-02 Last updated: 2015-10-05
In thesis
1. The Human Y chromosome and its role in the developing male nervous system
Open this publication in new window or tab >>The Human Y chromosome and its role in the developing male nervous system
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Recent research demonstrated that besides a role in sex determination and male fertility, the Y chromosome is involved in additional functions including prostate cancer, sex-specific effects on the brain and behaviour, graft-versus-host disease, nociception, aggression and autoimmune diseases. The results presented in this thesis include an analysis of sex-biased genes encoded on the X and Y chromosomes of rodents. Expression data from six different somatic tissues was analyzed and we found that the X chromosome is enriched in female biased genes and depleted of male biased ones. The second study described copy number variation (CNV) patterns in a world-wide collection of human Y chromosome samples. Contrary to expectations, duplications and not deletions were the most frequent variations. We also discovered novel CNV patterns of which some were significantly overrepresented in specific haplogroups. A substantial part of the thesis focuses on analysis of spatial expression of two Y-encoded brain-specific genes, namely PCDH11Y and NLGN4Y. The perhaps most surprising discovery was the observation that X and Y transcripts of both gene pairs are mostly expressed in different cells in human spinal cord and medulla oblongata. Also, we detected spatial expression differences for the PCDH11X gene in spinal cord. The main focus of the spatial investigations was to uncover genetically coded sexual differences in expression during early development of human central nervous system (CNS). Also, investigations of the expression profiles for 13 X and Y homolog gene pairs in human CNS, adult brain, testes and still-born chimpanzee brain samples were included. Contrary to previous studies, we found only three X-encoded genes from the 13 X/Y homologous gene pairs studied that exhibit female-bias. We also describe six novel non-coding RNAs encoded in the human MSY, some of which are polyadenylated and with conserved expression in chimpanzee brain. The description of dimorphic cellular expression patterns of X- and Y-linked genes should boost the interest in the human specific gene PCDH11Y, and draw attention to other Y-encoded genes expressed in the brain during development. This may help to elucidate the role of the Y chromosome in sex differences during early CNS development in humans.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 63 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1285
Keyword
MSY, sex differences, CNV, SNP, palindrome, palindromes, gr/gr duplication, gr/gr deletion, b2/b3 deletion, b2/b3 duplication, blue-grey duplication, blue-grey like duplication, IR2, U3, STS, AZFa, AZFb, AZFc, Olivary nucleus, Medulla oblongata, spinal cord, white matter, Affymetrix 6.0, embryo, embryonal, haplogroup, haplogroups, R1a, R1b, R-M207, E-M96, I-M170, J-M304, G-M201, Ashkenazi, Bolivian, Chinese, SNP array, padlock probing, AMY-tree
National Category
Genetics
Research subject
Biology with specialization in Animal Development
Identifiers
urn:nbn:se:uu:diva-261789 (URN)978-91-554-9331-8 (ISBN)
Public defence
2015-10-23, Zootissalen (EBC 01.01006), Evolutionsbiologiskt centrum, EBC, Villavägen 9, Uppsala, 13:15 (English)
Opponent
Funder
Swedish Research Council, K2012-61X-22089-01-3
Note

chinese, finnish, norwegian, schizophrenia, bipolar, bipolar disorder, msy, male specific region Y, PAR1, PAR2, pseudoautosomal, male-biased, female-biased, male biased, female biased, ashkenazi population, structure, variants, YHRD, Elena Jazin, Björn Reinius, Per Ahlberg, brain, hjärna, CNS, central nervous system, IR2, inverted repeat 2, isodicentric, genetics, genetik, padlock, rolling circle, amplification, PCR, sY1191, sY1291, STS, DDX3Y, DAZ, AZFa, AZFb, AZFc, AZF, Repping, haplogroup J, rearrangements, DE-M145, I-M170, E-M96, Q-M242, R-M207, O-M175, G-M201, D-M174, C-M130, NO-M214, N-M231, poland

Available from: 2015-10-02 Created: 2015-09-04 Last updated: 2015-10-23Bibliographically approved

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