ESPE2023 Free Communications Sex differentiation, gonads and gynaecology or sex endocrinology (6 abstracts)
Mapping the transcriptomic landscape of early human fetal ovary development through a clinically-focused lens
Sinead M McGlacken-Byrne 1 , Ignacio Del Torres 1 , Jenifer P Suntharalingham 1 , Federica Buonocore 1 , ICH HDBR 2 , Berta Crespo 2 , Nadjeda Moreno 2 , Ian C Simcock 3,4 , Owen Arthurs 3 , Theodoros Xenakis 1 , Paola Niola 5 , Tony Brooks 5 , Mehul T Dattani 1 & John C Achermann 1
1Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom. 2Developmental Biology and Cancer, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom. 3Department of Clinical Radiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom. 4Population, Policy and Practice Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom. 5UCL Genomics, Zayed Centre for Research, University College London, London, United Kingdom
Introduction: Ovary development was once considered a largely passive process. RNA sequencing (RNAseq) approaches have allowed us to begin to characterise ovary development in previously unparalleled detail, revealing the process to be complex and, still, little understood. A challenge is synthesising and using these data to advance our understanding of clinical disease. Through a clinically-focused lens, we elucidate novel aspects of the transcriptional landscape of the human fetal ovary across a critical period in early development.
Methods: We combined bulk RNA-seq (n=47)(19 ovaries, 20 testes, 8 control tissues between Carnegie Stage (CS) 22/23 and 15/16 weeks post conception (wpc); single nuclei RNA sequencing (snRNAseq) (n=2; 12wpc; 10,291 cells)(10X Genomics); micro-focus computed tomography (microCT; n=6); and macroscopic specimen examination (n=27 samples) to map gene expression and morphological change of early human fetal ovary development.
Results: Fetal ovary growth curves demonstrated that the ovary grows substantially in size during fetal development, with the increase in weight and length most marked from 17wpc. MicroCT shows that fetal ovaries move progressively anterolaterally within the abdomen between 12 and 19wpc. Bulk RNAseq revealed more differentially expressed genes (DEGs) in the fetal ovary compared to the testes at all developmental stages examined, most marked at meiosis (15/16wpc: n=1229 ovary DEGs; 632 testes DEGs; log2FC>2, p.adj<0.05). The fetal ovary is enriched for a distinct subset of transcription factors, including known (FOXL2, LIN28A), novel (ZIC1), and emerging ovary genes (DMRT2C, DMRTB1, MAEL) which localise to oogonia populations on snRNAseq analysis. Gene enrichment analysis of ovary DEGs revealed processes related to neurotransmitter signalling, neuroendocrine networks, and neural development; specific genes of interest included NPY, GABAergic genes (e.g., GABRG1), NAV3, and TAC1, localising to ovarian surface epithelial (OSE) snRNAseq populations. By overlapping ovary-specific DEGs at 15/16wpc with highly expressed genes from oogonia snRNAseq populations, new meiosis candidate genes were identified, including STRIP2, GBX1, TEX30, and NUP210L. Genes associated with mitochondrial metabolism were also highly expressed in the meiotic fetal ovary, including SLC25A31, OTUD6A, and DMN1L, localising to oogonia snRNAseq populations.
Conclusion: This work expands our knowledge of early human fetal ovary development. The ovary undergoes significant morphological change within a narrow time window.The ovary has a distinct transcriptomic signature and novel gene networks and signalling pathways are described. Genes important to early fetal ovary development are also important for later ovary function; these data will guide gene discovery in primary ovarian insufficiency and differences of sex development.
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