{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T06:23:41Z","timestamp":1769235821190,"version":"3.49.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T00:00:00Z","timestamp":1749081600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"Background<\/jats:title>Cathepsin D is an aspartic protease responsible for the proteolytic processing of vitellogenin at the early stages of folliculogenesis in oviparous vertebrates. Previously, we identified a multifunctional neuropeptide, tachykinin (TK), as an inducer of cathepsin D that promotes vitellogenic follicle growth in the ascidian Ciona intestinalis type A<\/jats:italic> (Ciona robusta<\/jats:italic>), a sister group of vertebrates. However, no regulatory factor for cathepsin D in the ovary has been identified in vertebrates. Moreover, the involvement of cathepsin D in mammalian folliculogenesis has yet to be investigated.<\/jats:p><\/jats:sec>Methods<\/jats:title>Ovaries of 2-week-old ICR mice were used. Cathepsin D<\/jats:italic> gene expression in the ovaries was examined by real-time PCR. Localization of cathepsin D was shown by immunostaining of ovarian sections. Cathepsin D activity was measured using supernatants from the homogenized ovaries. Mouse follicle growth was evaluated using three-dimensional follicle culture system.<\/jats:p><\/jats:sec>Results<\/jats:title>Immunohistochemical analysis revealed that cathepsin D is co-localized with TK receptors in granulosa cells of secondary follicles in the ovaries of two-week-old mice, which are sexually immature and in which the hypothalamus\u2013pituitary\u2013gonadal (HPG) axis is not yet functional. TK treatment of the ovaries significantly increased cathepsin D<\/jats:italic> gene expression and its proteolytic activity. Moreover, inhibition of cathepsin D markedly suppressed the secondary follicle growth.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>Collectively, these results indicate that cathepsin D plays essential roles in mouse secondary follicle growth. Recently, we also demonstrated that ovarian TKs promote secondary follicle growth in mice, primarily in a paracrine\/autocrine manner. Combined with these findings, the present study leads us to propose an evolutionary scenario in which TK\u2013cathepsin D signaling functions as a conserved mechanism for HPG axis-independent follicle growth across chordates, which may be more broadly conserved than the vertebrate-specific, HPG axis-dependent systems.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2025.1621348","type":"journal-article","created":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T04:11:12Z","timestamp":1749096672000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Cathepsin D mediates tachykinin-induced secondary follicle growth independent of the hypothalamic\u2013pituitary\u2013gonadal axis in 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