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

Casado-Navarro, R.; Bermejo-Santos, A.; Torrillas-de la Cal, R.; Madrigal, M. P.; Olive, V.; Chen-Chen, L. Y.; Amoros-Bru, S.; Jurado, S.; Serrano-Saiz, E.

doi:10.1101/2025.09.11.674830

bioRxiv · 10.1101/2025.09.11.674830

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

Casado-Navarro, R.·Bermejo-Santos, A.·Torrillas-de la Cal, R.·Madrigal, M. P.·Olive, V.·Chen-Chen, L. Y.·Amoros-Bru, S.·Jurado, S.·Serrano-Saiz, E.

View original source ↗Export metadata ↓

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.

Source connections

Published article ↗

Explore related subjects

developmental biology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Casado-Navarro, R., Bermejo-Santos, A., Torrillas-de la Cal, R., Madrigal, M. P., Olive, V., Chen-Chen, L. Y., Amoros-Bru, S., Jurado, S., Serrano-Saiz, E.. 2025-09-17. Expression Atlas Of Dmrt Genes Across Sex And Development: Functional Insights From The Mouse Olfactory System. https://doi.org/10.1101/2025.09.11.674830

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Neural regulation of hatching in amphibians

Many animal embryos hatch in response to threats or opportunities, yet how cue sensing activates hatching is unknown. We screened red-eyed treefrog (Agalychnis callidryas) eggs in the field with small molecules to discover that the neurotransmitter acetylcholine is a key mediator of hatching enzyme release. Using behavioral pharmacology, microscopy, and transcriptional profiling we identify direct cholinergic input on hatching gland cells that triggers enzyme release for egg rupture, and serotonergic transduction of embryonic hypoxia sensing. Independent hypoxia-sensing and mechanosensory predation-detection pathways converge on a hatching decision that elicits acetylcholine-dependent enzyme release and coordinated hatching-specific behavior. Cholinergic regulation of hatching enzyme release is conserved in a distantly related frog and salamander, suggesting a shared ancestral hatching mechanism. These results provide a neural basis for hatching plasticity which may have contributed to the evolution of diverse hatching modes in amphibians.

developmental biology↗

bioRxiv2026

Towards Understanding the Microenvironmental Control of Reindeer Antler Regeneration

Deer antlers are the only mammalian appendages capable of complete periodic regeneration and therefore provide a natural model for investigating mechanisms of skeletal regeneration. However, current knowledge of the structural and molecular characteristics of the regenerative antler microenvironment remains incomplete. Here, we compared antler tip and antler base tissues from Rangifer tarandus (reindeer) with mature metacarpal cortical bone using structural, compositional, histological, and proteomic analyses. Antler tissues exhibited smaller and less crystalline apatite structures, elevated carbonate substitution, and higher organic matrix content compared with metacarpal bone, indicating an immature mineral phase. Antlers also exhibited lower bone mineral density, greater porosity, reduced bone volume fraction, and greater trabecular separation, particularly in central regions, consistent with a dynamic remodeling microenvironment. Histological examination revealed abundant active osteons and extensive osteoid seams in antler tissues, whereas metacarpal bone predominantly comprised mature lamellar bone with limited remodeling activity. Proteomic profiling identified distinct extracellular matrix signatures between antler and metacarpal tissues. Metacarpal bone was enriched in proteins associated with skeletal homeostasis, mechanotransduction, and bone remodeling, whereas antler tissues were enriched in proteins involved in extracellular matrix reorganization, metabolic adaptation, and regeneration. Collectively, these findings indicate that reindeer antlers possess a specialized regenerative skeletal microenvironment characterized by immature mineral organization, active remodeling, and distinct molecular signatures associated with rapid tissue growth. These results provide new insights into the biological basis of mammalian appendage regeneration and may facilitate the development of regenerative strategies for bone repair and skeletal tissue engineering.

developmental biology↗

bioRxiv2026

Endogenous expression of mutant RagC in mice results in early-onset dilated cardiomyopathy with features of the Long-Olsen-Distelmaier syndrome

Dilated cardiomyopathy (DCM) is a severe heart condition often linked to arrhythmias, clots, and heart failure, for which treatments are not yet curative. Recently, de novo mutations in genes encoding components of the Rag GTPase nutrient signaling pathway, particularly in RRAGC, have been found in unrelated patients with a severe, early-onset DCM syndrome called Long-Olsen-Distelmaier. Cancer cell lines, hiPSC-derived cardiomyocytes and zebrafish have been used to study this Ragopathy, but a mammalian model to investigate this syndrome has not been generated. Here, we show that mice engineered to endogenously express mutations in Serine 74 (orthologous to the Serine 75 mutated in patients), exhibit early-onset features of DCM with decreased heart size, fibrosis, diastolic dysfunction and aortic insufficiency, characteristics reminiscent of the human syndrome. Moreover, Rragc-mutant hearts display decreased left ventricular mass and interventricular septum. Endogenous heterozygous expression of Rragc mutant variants result in a milder, sublethal defective physiological cardiac growth with increased systolic and diastolic blood pressure. Mechanistically, active RagC does not cause abnormal increase in cardiomyocyte size, but leads to suppressed transcriptional activity of Tfeb and alterations in cardiomyocyte metabolism. Transcriptional profiling of neonatal mutant hearts reveals multiple signatures of impaired mitochondrial activity. Ex vivo and in vitro analyses of murine cardiomyocyte mitochondria from Rragc-mutant mice show suppressed mitochondrial respiration, disturbed complex IV multimerization and super-complex organization. These data point to abnormal early postnatal heart metabolism by deregulated nutrient - Rag GTPase signaling with a potential molecular explanation to the early onset of DCM in patients with de novo missense mutations in RRAGC, and suggests the relevance of early metabolic interventions in conditions with altered nutrient signaling

developmental biology↗