ESPE Yearbook of Paediatric Endocrinology

Nature. 2024 Nov;635(8040):960-968. doi: 10.1038/s41586-024-08104-6

Brief summary: This study investigated how the presence of an extra X chromosome in Klinefelter syndrome (47,XXY) affects the development of male fetal germ cells. Using single-cell RNA sequencing and epigenetic profiling of human fetal testes, the authors found that male germ cells with an extra X chromosome exhibit aberrant gene expression, impaired cell cycle regulation, and defective epigenetic reprogramming. They have shown a widespread transcriptional dysregulation in XXY germ cells, including activation of stress and apoptotic pathways. Their findings suggested that human fetal germ cells do not re-establish X-inactivation after X chromosome reactivation (XCR), resulting inpersistent expression from two active X chromosomes. Additionally impaired DNA methylation dynamics and chromatin remodeling compromise germ cell maturation and subsequently many XXY germ cells are eliminated before completing differentiation. Especially, WNT pathway and TGF-β pathway (particularly the NODAL signalling pathway) genes were upregulated which have an important role in maintaining the naive state of fetal germ cells. They have shown that inhibition of the TGF-β pathway improves the differentiation of fetal germ cells in Klinefelter syndrome.

This study provides a detailed molecular map of development of fetal germ cell in Klinefelter syndrome, identifying stage-specific transcriptional defects. It highlights the unique epigenetic behavior of human fetal germ cells, contrasting with mouse models where X-inactivation is more tightly regulated. The rescue experiment with TGF-β inhibition adds translational value and opens the door for interventional strategies in KS-related infertility. However, the long-term functional competence of rescued fetal germ cell (via TGF-β inhibition) was not addressed, and the questions remains whether these cells can give rise to functional spermatogonia or sperm? Additionally, therapeutic translation is promising but issues like safety, timing, and specificity of pathway inhibition need substantial further investigation.