Abstract
The ancient DMRT family of transcription factors has been proposed as evolutionarily conserved effectors of sexual differentiation. While brain sexual differentiation has traditionally been attributed to a paracrine role of steroid hormones and intrinsic cues directly controlled by sex chromosomes, the downstream effector mechanisms remain elusive. To elucidate the role of Dmrts in mammalian brain sexual differentiation, we generated a comprehensive expression atlas for all family members in the mouse brain using in situ hybridization across sexes and development (E12.5, E14.5, E18.5, adulthood and, sometimes, P7). We found that all Dmrts, except Dmrt7, were expressed in the brain. This study expands understanding of the DMA-Dmrt subfamily beyond pallial structures and identifies their expression maintenance in adult neurogenic sites. For the first time, we described the neuronal expression of Dmrt2 and Dmrt6. Mouse Dmrts did not show clear sexually dimorphic patterns, but did show quantitative expression differences between sexes. Most Dmrts were maintained in postmitotic neurons during embryonic and postnatal stages, suggesting potential interactions with gonadal sex hormones during organizational (perinatally, with testosterone peaking at E18.5 in males) and activational phases (after puberty, with androgens in males and estrogens in females). Our analysis of Dmrt5 expression revealed its prominent presence in the mouse olfactory system. The olfactory system shows sex differences and is fundamental for controlling sex-specific innate behaviors in rodents. Thus, it represents an ideal scenario to test, as a proof of concept, the role of Dmrts in the sexual differentiation of the mammalian brain. The absence of Dmrt5 similarly affected the main olfactory epithelium, where sensory neurons reside, in both sexes; however, cell number-related defects in the olfactory bulb and piriform cortex differed between male and female embryos, revealing Dmrt5 interaction with sex in deeper layers of innate neural circuits. Our results provide a valuable resource for uncovering novel sites and mechanisms of sexual differentiation in the mammalian nervous system, potentially contributing to sex biases observed in psychiatric and neurological disorders.