Expression Atlas Of Dmrt Genes Across Sex And Development: Functional Insights From The Mouse Olfactory System

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 the sex chromosome complement (XX or XY) and steroid sex hormones, the downstream effector mechanisms controlled by these factors remain elusive. To elucidate the role of Dmrts in the mammalian brain sexual differentiation, we generated a comprehensive expression atlas for all family members (Dmrt1-7) in the mouse brain. We used in situ hybridization to examine both sexes across various developmental stages. Our findings revealed that all Dmrts, except Dmrt7, are expressed in the brain. This study expands our 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 exhibit clear sexually dimorphic patterns but showed quantitative differences in expression levels between the sexes. We demonstrated that most Dmrts are maintained in postmitotic neurons during both embryonic and postnatal stages, suggesting potential interactions with steroid hormones during organizational and activational phases. As proof of concept, our comprehensive analysis of Dmrt5 expression revealed its prominent presence in the mouse olfactory system, which is fundamental for controlling sex-specific innate behaviors. The absence of Dmrt5 affects the main olfactory epithelium, where sensory neurons are located; however, mis-patterning phenotypes observed in the olfactory bulb and the piriform cortex distinctly affect male and female embryos, revealing the interaction of Dmrt5 with sex in deeper integrative 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 the sex bias observed in the prevalence and symptomatology of psychiatric disorders.