Transcriptomic sex differences in early human fetal brain development
The influence of sex chromosomes and sex hormones on early human brain development is poorly understood. We therefore undertook transcriptomic analysis of 46,XY and 46,XX human brain cortex samples (n = 64) at four different time points between 7.5 and 17 weeks post conception (wpc), in two independent studies. This developmental period encompasses the onset of testicular testosterone secretion in the 46,XY fetus (8wpc). We show differences in sex chromosome gene expression including X-inactivation genes (XIST, TSIX) in 46,XX samples; core Y chromosome genes (n = 18) in 46,XY samples; and two Y chromosome brain specific genes, PCDH11Y and RP11-424G14.1. PCDH11Y (protocadherin11 Y-linked) regulates excitatory neurons; this gene is unique to humans and is implicated in language development. RP11-424G14.1 is a long non-coding RNA. Fewer differences in sex hormone pathway-related genes are seen. The androgen receptor (AR, NR3C4) shows cortex expression in both sexes, which decreases with age. Global cortical sex hormone effects are not seen, but more localized AR mechanisms may be important with time (e.g., hypothalamus). Taken together, our data suggest that limited but potentially important sex differences occur during early human fetal brain development.
Authors
- John C. Achermann (ORCID: https://orcid.org/0000-0001-8787-6272)
- Federica Buonocore (ORCID: https://orcid.org/0000-0002-8274-7241)
- Ignacio del Valle (ORCID: https://orcid.org/0000-0003-2595-3652)
- Jenifer P. Suntharalingham (ORCID: https://orcid.org/0000-0002-8897-7697)
- Nadjeda Moreno (ORCID: https://orcid.org/0009-0001-6385-2257)
- Paola Niola (ORCID: https://orcid.org/0000-0002-3377-5991)
- Olumide Ogunbiyi (ORCID: https://orcid.org/0000-0001-5208-5526)
- Mehul Dattani (ORCID: https://orcid.org/0000-0002-0365-5809)
- Nita Solanky (ORCID: https://orcid.org/0000-0001-8304-5543)
- Aragorn Jones (ORCID: https://orcid.org/0000-0002-4255-2482)
- Tony Brooks
Institutions
- Great Ormond Street Hospital for Children NHS Foundation Trust (GB)
- Institute of Child Health (IN)
- University College London (GB)
- Newcastle University (GB)
Publication Details
- Journal
- Communications Biology
- Published
- 2025-04-25
- DOI
- https://doi.org/10.1038/s42003-025-08070-3
- Citations
- 5
- Primary Topic
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Type
- article
- Field-Weighted Citation Impact
- 9.09
Funders
- Wellcome
- Wellcome Trust
- National Institute for Health and Care Research
- National Institutes of Health
- Medical Research Council
- Great Ormond Street Institute of Child Health
- NIHR Great Ormond Street Hospital Biomedical Research Centre
- National Heart, Lung, and Blood Institute
- National Institute of Mental Health
- National Institute on Drug Abuse
- National Human Genome Research Institute
- NIH Office of the Director
- National Cancer Institute
- National Institute of Neurological Disorders and Stroke
- Common Fund