Decoding Dmrt1: Insights into vertebrate sex determination and gonadal sex differentiation

Abstract

The Dmrt gene family is characterized by a conserved DM domain. It includes nine genes in vertebrates 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. Dmrt1, or Sox9, forms a conserved antagonistic interaction with Foxl2 (crucial for ovarian formation) across mammals. Across 128 vertebrate species, Dmrt1 exhibits sexually dimorphic expression, prior to and during gonadal sex differentiation and in adult testes, implicating its role in master regulation of sex determination and gonadal sex differentiation. Dmrt1 emerges as a master/upstream 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 non-coding RNA involvement, in a wide spectrum of sex-determining mechanisms ranging from genetic factors, to interactions between genetic factors with the environment, to solely environmental factors. 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 highly conserved 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 the molecular basis of epigenetic regulation. It is also essential to understand why and how multiple alternative splicing variants of Dmrt1 evolve in vertebrates, the specific roles each isoform plays in sex determination and gonadal sex differentiation, 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.

Graphical Abstract

Dmrt1, DM domain, sex determination, gonadal sex differentiation, master sex-determining gene, GSD, ESD, epigenetic regulation, alternative splicing, vertebrates

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