Cholecystokinin coordinates gonadotropin-dependent and independent pathways to orchestrate zebrafish gonadal development

Cholecystokinin (CCK) is established as a critical regulator of teleost gonadal development, functioning not only as a follicle-stimulating-hormone-releasing hormone (FSH-RH) but also stimulating gonadal development through three distinct mechanisms. Specifically, (1) CCK directly activates pituitary lhb transcription via CCKBRb in a specific bi-hormonal subpopulation, and indirectly enhances hypothalamic gnrh3 expression to regulate LH synthesis and secretion. However, CCK's physiological role in LH regulation requires further investigation, and its effect may involve both direct and indirect mechanisms, including targeting a specific bi-hormonal subpopulation. (2) CCK exerts gonadotropin-independent control over primordial germ cell (PGC) proliferation during embryogenesis, evidenced by significantly reduced PGC numbers in cck1^-/-;cck2^-/- and cckbrb^-/- mutants, a phenotype absent in fshb^-/- and lhb^-/-;fshb^-/- zebrafish. (3) CCK initiates meiosis and maintains gonadal somatic cell survival by suppressing apoptosis; these processes are abrogated in CCK-deficient mutants but remain intact in gonadotropin-deficient lines. Collectively, hypothalamic and peripheral CCK cells regulate gonadal function through gonadotropin-dependent and gonadotropin-independent pathways, respectively, thereby coordinating gonadal development from germline establishment to maturation.