Somatic Transthyretin-Related Proteins in C. elegans Govern Reproductive Longevity by Sustaining Sperm Integrity and Timely Ovulation

Abstract

The decline in reproductive capability during adult life is critical for health, but its mechanism is elusive. We systematically analyzed the developmental role of an expanded TTR family of proteins, structurally analogous to mammalian thyroid hormone-transporting Transthyretin, and identified three paralogous proteins, TTR-15, TTR-16, and TTR-17, differentially expressed in somatic cells of the gonads and secreted around gametes in C. elegans. Simultaneous inactivation of TTR-15, TTR-16, and TTR-17 leads to a rapid reduction in reproductive capacity in middle age. While oocyte and sperm production remain unaffected in the triple mutants, late-onset infertility results from stalled ovulation. Mechanistically, the absence of TTR-15, TTR-16, and TTR-17 causes sperm to prematurely deplete the cytoplasmic pool of major sperm protein (MSP), released via non-conventional vesicle budding as a signal for ovulation. We propose that the somatic gonads play a central role in maintaining sperm integrity post-production and determining the duration of the reproductive age. HighlightsO_LISystematic analysis of TTR family proteins reveals diverse expression and critical functions. C_LIO_LITTR-15, TTR-16, and TTR-17 are secreted around gametes in C. elegans. C_LIO_LITTR-15/16/17 triple KO exhibits middle-age onset infertility due to stalled ovulation. C_LIO_LIMSP, a signal for ovulation, is prematurely depleted from sperm in the absence of TTR-15/16/17. C_LI