Biology subjects

Torrillas-de la Cal, R.

Publications and source records attributed to Torrillas-de la Cal, R..

3 recordsLinked to original sources

bioRxiv2026

MT4-MMP/NRP1 axis is required for balanced angiogenesis in the embryonic brain

Angiogenesis is essential for embryonic brain development and tissue repair, yet the mechanisms that spatiotemporally coordinate endothelial behavior to ensure balanced vascular remodeling remain elusive. Here, we identify the glycosylphosphatidylinositol (GPI)-anchored protease MT4-MMP as a critical, context-dependent determinant of angiogenic growth. Global loss of MT4-MMP transiently impairs vascular network formation in the embryonic hindbrain, whereas endothelial-specific deletion triggers an aberrant angiogenesis characterized by increased vessel density, branching, and a profound loss of vascular organization. This dual phenotype reveals MT4-MMP as a fundamental coordinator of neurovascular development. Consistently, MT4-MMP expression was dynamically regulated during wound repair, and its absence amplifies angiogenesis and accelerates wound closure in adult skin, highlighting its role in maintaining vascular homeostasis postnatally. Mechanistically, MT4-MMP-deficient endothelial cells exhibit impaired polarization and sustained, rather than transient, VEGFA-induced ERK activation. We identify NRP1 as a novel substrate of MT4-MMP and demonstrate that MT4-MMP-mediated NRP1 cleavage restricts NRP1 surface availability to tune the intensity of VEGFA signaling. Furthermore, pharmacological blockade of VEGFA-NRP1 binding partially rescues the vascular defects caused by endothelial MT4-MMP loss in vivo. Together, these findings uncover the MT4-MMP/NRP1 axis as a pivotal control point that prevents aberrant vessel expansion, establishing membrane-anchored proteolysis as a primary regulator across developmental and reparative contexts. TeaserThe proteolytic constraint exerted by MT4-MMP dictates neurovascular development and wound repair through the spatial control of NRP1-VEGFA signaling.

cell 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↗