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Male sex hormones increase excitatory neuron production in developing human neocortex

View ORCID ProfileIva Kelava, Ilaria Chiaradia, Laura Pellegrini, Alex T. Kalinka, View ORCID ProfileMadeline A. Lancaster
doi: https://doi.org/10.1101/2020.10.24.353359
Iva Kelava
1MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK
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  • ORCID record for Iva Kelava
  • For correspondence: madeline.lancaster@mrc-lmb.cam.ac.uk ikelava@mrc-lmb.cam.ac.uk
Ilaria Chiaradia
1MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK
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Laura Pellegrini
1MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK
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Alex T. Kalinka
2Milner Therapeutics Centre, University of Cambridge, Cambridge Biomedical Campus, Puddicombe Way, Cambridge, CB2 0AW, UK
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Madeline A. Lancaster
1MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK
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  • ORCID record for Madeline A. Lancaster
  • For correspondence: madeline.lancaster@mrc-lmb.cam.ac.uk ikelava@mrc-lmb.cam.ac.uk
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Abstract

The presence of male-female brain differences has long been a controversial topic. Yet simply negating the existence of biological differences has detrimental consequences for all sexes and genders, particularly for the development of accurate diagnostic tools, effective drugs and understanding of disease. The most well-established morphological difference is size, with males having on average a larger brain than females; yet a mechanistic understanding of how this difference arises remains to be elucidated. Here, we use brain organoids to test the roles of sex chromosomes and sex steroids during development. While we show no observable differences between XX and XY brain organoids, sex steroids, namely androgens, increase proliferation of cortical neural progenitors. Transcriptomic analysis reveals effects on chromatin remodelling and HDAC activity, both of which are also implicated in the male-biased conditions autism spectrum disorder and schizophrenia. Finally, we show that higher numbers of progenitors result specifically in increased upper-layer excitatory neurons. These findings uncover a hitherto unknown role for male sex hormones in regulating excitatory neuron number within the human neocortex and represent a first step towards understanding the origin of human sex-related brain differences.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted October 24, 2020.
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Male sex hormones increase excitatory neuron production in developing human neocortex
Iva Kelava, Ilaria Chiaradia, Laura Pellegrini, Alex T. Kalinka, Madeline A. Lancaster
bioRxiv 2020.10.24.353359; doi: https://doi.org/10.1101/2020.10.24.353359
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Male sex hormones increase excitatory neuron production in developing human neocortex
Iva Kelava, Ilaria Chiaradia, Laura Pellegrini, Alex T. Kalinka, Madeline A. Lancaster
bioRxiv 2020.10.24.353359; doi: https://doi.org/10.1101/2020.10.24.353359

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