Biology subjects

Serrano-Saiz, E.

Publications and source records attributed to Serrano-Saiz, E..

4 recordsLinked to original sources

bioRxiv2026

A signaling network motif couples protein expression levels and intracellular localization

Most of the accepted major signaling pathways incorporate a mechanism of physical separation of active versus inactive effector proteins, in the form of dynamic nucleocytoplasmic shuttling. Here, we show that when this translocation takes place as dimers, it operates as a network motif that introduces a nonlinear coupling between expression levels of a protein and its intracellular localization. This mechanism modulates the activity of the TGF-{beta} signaling cascade by affecting the location of its main effectors, the R-Smads, as well as in all signaling cascades analyzed that incorporate a dimerization step linked to nucleocytoplasmic shuttling, operating as a singular type of nonlinear network motif that does not require a loop of regulation and takes advantage of physical intracellular compartmentalization.

systems biology↗

bioRxiv2025

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

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.

developmental biology↗

bioRxiv2025

Dmrt2 Orchestrates Neuronal Development in the Embryonic Cingulate Cortex: Unveiling Sex-Biased Vulnerabilities

Sexual differences are prevalent in the brain. DMRT transcription factors have been postulated as important determinants of sex differences. Previous research focused on the DMA subfamily in the brain. Here, we reveal an unprecedented role for Dmrt2 in regulating the proliferation and development of cortical neurons in mice. Dmrt2 is expressed in deep-layer neurons of the cingulate cortex (CgCx) throughout development. Its downregulation in the CgCx primordium results in premature cell cycle exit of embryonic progenitors and subsequent reduction in cortical plate cellular density at later developmental stages. Dmrt2 expression is higher in male embryos during early development, potentially explaining their increased vulnerability to Dmrt2 depletion. As development progresses, Dmrt2 expression persists in deep-layer neurons, controlling processes like migration, axonal targeting, and neuronal-specific gene expression. This study broadens our understanding of Dmrt2 gene function in the brain and provides insights into the molecular basis of sexual differences in neurodevelopmental processes.

developmental biology↗

bioRxiv2018

Timing mechanism of sexually dimorphic nervous system differentiation

In all animals, sexual differentiation of somatic tissue is precisely timed, yet the molecular mechanisms that control the timing of sexual differentiation, particularly in the brain, are poorly understood. We have used sexually dimorphic molecular, anatomical and behavioral features of the C. elegans nervous system to decipher a regulatory pathway that controls the precise timing of sexual differentiation. We find that the sexually dimorphic differentiation of postmitotic neurons in the male nervous system is abrogated in animals that carry a mutation in the miRNA let-7 and prematurely executed in animals either lacking the let-7 inhibitor lin-28, or the direct let-7 target lin-41, an RNA-binding, posttranscriptional regulator. We show that an isoform of a phylogenetically conserved transcription factor, lin-29a, is a critical target of LIN-41 in controlling sexual maturation of sex-shared neurons. lin-29a is expressed in a male-specific manner in a subset of sex-shared neurons at the onset of sexual maturation. lin-29a acts cell-autonomously in these neurons to control the expression of sexually dimorphic neurotransmitter switches, sensory receptor expression, neurite anatomy and connectivity, and locomotor behavior. lin-29a is not only required but also sufficient to impose male-specific features at earlier stages of development and in the opposite sex. The temporal, sexual and spatial specificity of lin-29a expression is controlled intersectionally through the lin-28/let-7/lin-41 heterochronic pathway, sex chromosome configuration and neuron type-specific terminal selector transcription factors. Two Doublesex-like transcription factors represent additional neuron-type specific targets of LIN-41 and are regulated in a similar intersectional manner, indicating the existence of modular outputs downstream of the heterochronic pathway. In conclusion, we have provided insights into the molecular logic of the timing of sexual differentiation in the C. elegans nervous system. Remarkably, the lin28/let7 axis also controls the timing of sexual differentiation in mice and humans thereby hinting toward a striking universality of the control mechanisms of sexual differentiation.

neuroscience↗