Sex and the singular DM domain: insights into sexual regulation, evolution and plasticity

Abstract

Most animals reproduce sexually, but the genetic and molecular mechanisms that determine the eventual sex of each embryo vary remarkably. DM domain genes, which are related to the insect gene doublesex, are integral to sexual development and its evolution in many metazoans. Recent studies of DM domain genes reveal mechanisms by which new sexual dimorphisms have evolved in invertebrates and show that one gene, Dmrt1, was central to multiple evolutionary transitions between sex-determining mechanisms in vertebrates. In addition, Dmrt1 coordinates a surprising array of distinct cell fate decisions in the mammalian gonad and even guards against transdifferentiation of male cells into female cells in the adult testis.

Figure 1. DM domain genes in metazoan sexual development

a | Metazoan phylogeny showing phyla in which DM domain genes have been implicated in sexual development, either through functional analysis or sex-biased expression (highlighted in red). b | Arthropod phylogeny showing taxa in which a doublesex (dsx) gene has been shown to be required for sexual differentiation (highlighted in red). Sex-determining mechanisms of species shown to require dsx are indicated by the letters placed next to the name of the taxon. Note that many other sex-determining mechanisms are found in most of these taxa but are not known to involve a dsx-like gene. c | Vertebrate phylogeny showing taxa in which a Dmrt1 homologue is required for sex determination (highlighted in red). In teleost fish and in amphibians, many other sex-determining mechanisms occur, but the role of Dmrt1 is unknown in most of these. ESD, environmental sex determination; HD, haplodiploid system in which females are haploid (from unfertilized eggs), and males are diploid (from fertilized eggs); XY, male heterogamety with XY males and XX females; ZW, female heterogamety system with ZZ males and ZW females.

Figure 2. Diverse roles of DMRT1 orthologues in vertebrate sex determination

Blue shading indicates masculinizing function and pink indicates feminizing function. a | In mammals, expression of the X-chromosome-linked sex-determining region of chromosome Y (SRY) gene in the fetal gonad triggers male development by activating SOX9 transcription during a crucial period and, in the absence of SOX9 activation, ovarian development ensues. DMRT1 is expressed in the fetal gonad in mammals before sex determination but is required only after gonadal sex is determined. b | In medaka, a Y-chromosome-linked, recently duplicated Dmrt1 gene, DM domain on Y (Dmy; also known as Dmrt1bY), has a role that is analogous to that of SRY, triggering testis development in XY fish. c | In birds, Dmrt1 is Z-chromosome-linked and thus genetic males have two copies, whereas females have one. Dmrt1 expression is much higher in the genital ridge of ZZ birds, and Dmrt1 is required for testis determination, suggesting that testis fate requires a critical threshold of Dmrt1 activity. d | In the frog Xenopus laevis, a duplicated and truncated Dmrt1 gene (dmw) is found on the female-specific W chromosome and appears to block the ability of the autosomal Dmrt1 gene to determine testis fate. In medaka, birds and X. laevis, the autosomal Dmrt1 genes also are believed to function in testicular differentiation after gonadal sex is determined, similar to the situation for their mammalian counterparts.