DMRT1: An Ancient Sexual Regulator Required for Human Gonadogenesis

Transcriptional regulators related to the invertebrate sexual regulators <i>doublesex</i> and <i>mab-3</i> occur throughout metazoans and control sex in most animal groups. Seven of these <i>DMRT</i> genes are found in mammals, and mouse genetics has shown that one, <i>Dmrt1</i>, plays a crucial role in testis differentiation, both in germ cells and somatic cells. Deletions and, more recently, point mutations affecting human <i>DMRT1</i> have demonstrated that its heterozygosity is associated with 46,XY complete gonadal dysgenesis. Most of our detailed knowledge of DMRT1 function in the testis, the focus of this review, derives from mouse studies, which have revealed that DMRT1 is essential for male somatic and germ cell differentiation and maintenance of male somatic cell fate after differentiation. Moreover, ectopic DMRT1 can reprogram differentiated female granulosa cells into male Sertoli-like cells. The ability of DMRT1 to control sexual cell fate likely derives from at least 3 properties. First, DMRT1 functionally collaborates with another key male sex regulator, SOX9, and possibly other proteins to maintain and reprogram sexual cell fate. Second, and related, DMRT1 appears to function as a pioneer transcription factor, binding “closed” inaccessible chromatin and promoting its opening to allow binding by other regulators including SOX9. Third, DMRT1 binds DNA by a highly unusual form of interaction and can bind with different stoichiometries.

Evolutionary dynamics of cytoplasmic segregation and fusion: mitochondrial mixing facilitated the evolution of sex at the origin of eukaryotes

Sexual reproduction is a trait shared by all complex life, but explaining its origin and evolution remains a major theoretical challenge. Virtually all theoretical work on the evolution of sex has focused on the benefits of reciprocal recombination among nuclear genes, paying little attention to the dynamics of mitochondrial genes. Here I develop a mathematical model to study the evolution of alleles inducing cell fusion in an ancestral population of clonal proto-eukaryotes. Mitochondrial mixing masks the detrimental effects of faulty organelles and drives the evolution of sexual cell fusion despite the declining long-term population fitness. Cell-fusion alleles fix under negative epistatic interactions between mitochondrial mutations and strong purifying selection, low mutation load and weak mitochondrial-nuclear associations. I argue that similar conditions could have been maintained throughout the eukaryogenesis, favoring the evolution of sexual cell fusion and meiotic recombination without compromising the stability of the emerging complex cell.