Seminar "The Role of the Maternal Nutrition–Placenta–Fetal Epigenome Axis in Mammalian Sex Determination"

Speaker: Prof. Makoto Tachibana, Graduate School of Frontier Biosciences, The University of Osaka

Title: The Role of the Maternal Nutrition–Placenta–Fetal Epigenome Axis in Mammalian Sex Determination

Abstract:
In sexually reproducing organisms, the developmental fate of the initially bipotential gonad is determined during a specific embryonic period. This process, known as sex determination, establishes whether the gonad will develop into a testis or an ovary and represents a fundamental developmental event that subsequently governs gametogenesis and sexual dimorphism throughout the body. In mammals, the Y-linked gene SRY/Sry (Sex-determining Region Y) functions as the master regulator of male sex determination. In mice, Sry expression is restricted to a remarkably narrow developmental window, peaking at embryonic day 11.5 (E11.5), and is confined to a limited population of supporting cell precursors within the developing gonad. Although such precisely regulated spatiotemporal expression of Sry is essential for testis determination, the molecular mechanisms underlying its regulation remained largely unknown for many years.

In 2013, we demonstrated that epigenetic regulation mediated by a histone demethylase is indispensable for Sry activation in mice. Subsequent analyses revealed that genes encoding rate-limiting enzymes in multiple metabolic pathways are significantly enriched in Sry-expressing XY supporting cell precursors, suggesting a close link between intracellular metabolic status and male sex determination. In this seminar, I will present our recent findings on the role of iron metabolism in mouse sex determination, reported last year, and discuss emerging evidence for the regulation of sex determination through the maternal nutrition–placenta–fetal epigenome axis.

References

1. Kuroki S et al., (2013) Epigenetic regulation of mouse sex determination by the histone demethylase Jmjd1a. Science 341:1106-1109
2. Kuroki S et al., (2017) Rescuing the aberrant sex development of H3K9 demethylase Jmjd1a-deficeint mice by modulating H3K9 methylation balance. PLoS Genet e1007034 
3. Miyawaki S et al., (2020). The mouse Sry locus harbors a cryptic exon that is essential for male sex determination. Science 370:121-124
4. Okashita N et al., (2025) Maternal iron deficiency causes male-to-female sex reversal in mouse embryos. Nature 643:262-270