ESPE Abstracts (2023) 97 RFC7.5

1Genetics and Genomic Medicine Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom. 2Developmental Biology and Cancer Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom

Introduction: The influence of sex chromosomes and sex hormones on early human brain development is still poorly understood. Expression of Y chromosome genes may influence aspects of brain maturation in the 46,XY fetus, but the contribution of different Y genes is unknown. Furthermore, a marked increase in testicular testosterone biosynthesis/release from the testis occurs at around 8 weeks post conception (wpc) in the 46,XY fetus, but it is unclear whether testosterone gets converted to dihydrotestosterone in the brain, and when/where androgen receptors (AR) are expressed.

Aims: We aimed to study global sex differences in gene expression and components of the androgen pathway in early human fetal brain cortex development.

Methods: Two independent datasets of fetal brain cortex samples were used (Brain-Seq1 and Brain-Seq2), each having a total of four 46,XY and four 46,XX samples at specific time points of development: CS22-23 (7.5-8wpc), 9wpc, 11-12wpc, 15-17wpc (32 samples in each dataset; total n=64). Total RNA was extracted and bulk RNA-sequencing was carried out in Brain-Seq1. RNA-sequencing data for Brain-Seq2 was obtained from the Human Developmental Biology Resource. Principle components analysis (PCA) and differential gene expression analysis were undertaken in R using the DESeq2 bioinformatic package. Matched control tissue analysis determined brain specificity. Public repositories of brain single-cell RNA-sequencing data were also analysed.

Results: PCA showed a major contribution of karyotype to PC2 (19-20%). By overlaying differential gene expression patterns (46,XY versus 46,XX) across stages in both datasets, we identified a “core” group of 18 differentially expressed Y chromosome genes in the developing 46,XY brain. Of these, PCDH11Y - a gene unique to humans - showed high brain specificity, and is enriched in adult brain (HPA and GTEx consensus dataset). The only consistently differentially expressed genes in the 46,XX brain were XIST and TSIX, X-chromosome inactivation regulators. Analysis of global AR expression in telencephalon/cortex showed a stepwise decrease in both sexes across time. Minimal/no expression of SRD5A2 was observed, although SRD5A1 and SRD5A3 were expressed. Analysis of single-cell repositories revealed more localised developmental AR expression in pituitary corticotropes and hypothalamic supramammillary nucleus during development.

Conclusion: Human fetal brain cortex gene expression patterns showed global sex differences, influenced by Y chromosome genes and X-inactivation regulators, but the biological effect at this early stage is unclear. Relative AR expression in the cortex decreased in both sexes across this critical time course, with localised AR expression emerging in key regions influencing endocrine regulation.

Volume 97

61st Annual ESPE (ESPE 2023)

The Hague, Netherlands
21 Sep 2023 - 23 Sep 2023

European Society for Paediatric Endocrinology 

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