Decoding <i>Dmrt1</i>: insights into vertebrate sex determination and gonadal sex differentiation

The Dmrt gene family is characterized by a conserved DM domain, and is crucial to sex determination and sexual differentiation. Dmrt1 is pivotal in testis formation and function by interacting with genes crucial for Sertoli cell differentiation, such as Sox9. Across 128 vertebrate species, Dmrt1 exhibits sexually dimorphic expression, prior to gonadal sex differentiation, implicating its role in master regulation of sex determination. Dmrt1 emerges as a master sex-determining gene in one fish, frog, chicken, and turtle, with candidacy in 12 other vertebrate species. Recent studies suggest epigenetic regulation of Dmrt1 in its promoter methylation, and transposable element insertion introducing epigenetic modification to cis-regulatory elements of Dmrt1, alongside noncoding RNA involvement, in sex-determining mechanisms. Additionally, alternative splicing of Dmrt1 was found in all major vertebrate groups except amphibians. Dmrt1 has evolved many lineage-specific isoforms (ranging from 2 to 10), and various isoforms showed sex, tissue, or development-specific expression, which is in contrast to the sex-specific splicing of its homolog Dsx across insects. Future research should focus on understanding the molecular basis of environmental sex determination from a broader taxon, and that of epigenetic regulation. It is also essential to understand why and how alternative splicing variants of Dmrt1 evolve in vertebrates, the specific roles each isoform plays, as well as the significant differences in the molecular mechanisms and functions of alternative splicing between Dmrt1 in vertebrates and Dsx in insects. Understanding the differences could provide deeper insights into the evolution of sex-determining mechanisms between vertebrates and insects.