Zglp-1 is a novel essential transcriptional regulator for sex reversal in zebrafish.

Sex determination and differentiation play crucial biological roles in sexual reproduction in vertebrates, including zebrafish. Nevertheless, the intricate molecular mechanisms governing these processes have remained enigmatic. In this study, we showed a pivotal role played by zinc finger GATA-like protein-1 (Zglp-1) in sex differentiation in zebrafish. Our findings revealed that homozygous mutants having no Zglp-1 exhibited a female-to-male sex reversal, ultimately resulting in the development of fertile males. Within the pivotal phase of sexual differentiation, zglp-1 (-/-) zebrafish demonstrated a gene expression pattern that was skewed toward a male phenotype. Notably, the expression of amh was upregulated, while the expression of cyp19a1a was not sustained. Furthermore, our data revealed a direct interaction between the zinc fingers of Zglp-1 and Sf-1, which inhibited the ability of Sf-1 to activate the amh promoter. This interaction was crucial for regulating sex differentiation. Moreover, we observed alterations in gonadal cell proliferation and apoptosis in zglp-1 (-/-) zebrafish, which partially contributed to the sexual fate selection. Overall, our findings firmly established Zglp-1 as a crucial regulator of sex differentiation in zebrafish, offering deep insights into the intricate molecular mechanisms that govern sex determination and differentiation in vertebrates. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s42995-025-00299-5.