Biology subjects

Barrionuevo, F. J.

Publications and source records attributed to Barrionuevo, F. J..

3 recordsLinked to original sources

bioRxiv2024

Sox9 prevents retinal degeneration and is required for limbal stem cell differentiation in the adult mouse eye

Sox9 is a transcription factor with multiple roles during development and in adult organ homeostasis. In the adult eye, Sox9 expression persists in several cell types, including the retinal pigmented epithelium cells and the Muller glial cells, as well as in the limbal and corneal basal epithelia. To uncover the role of Sox9 in these cell types, we induced the deletion of the gene in adult mice. We found that, after Sox9 ablation, mutant mice undergo a severe process of retinal degeneration characterized by the loss of Muller glial cells and complete depletion of the photoreceptors layer. Moreover, by combining single-cell RNA sequencing and Sox9 lineage tracing, we found that Sox9 is expressed in a basal limbal stem cell population with the ability to form two types of long-lived cell clones involved in stem cell maintenance and homeostasis. Mosaic analysis of Sox9 positive and negative cells confirmed that the gene is essential for limbal stem cell differentiation. Our results show that Sox9 is required for the maintenance of retinal integrity and for limbal stem cell differentiation in the adult mouse eye.

developmental biology↗

bioRxiv2023

Complete male-to-female sex reversal in XY mice lacking the miR-17~92 cluster

In mammals, sex determination is controlled by antagonistic gene cascades operating in embryonic undifferentiated gonads1 2. The expression of the Y-linked gene SRY is sufficient to trigger the testicular pathway, whereas its absence in XX embryos leads to ovarian differentiation3 4 5. Despite this strong genetic component, the involvement of non-coding regulation in determining mammalian sex remains unclear6. Here we show that the deletion of a single microRNA cluster, miR-17[~]92, induces complete primary male-to-female sex reversal in XY mice. Time-course analyses revealed that Sry is heterochronically expressed, showing a delay in XY miR-17[~]92 knockout gonads, which subsequently activate the ovarian genetic program. Bulk and single cell RNA-seq analyses showed that Sertoli cell differentiation is reduced, delayed and unable to sustain the testicular fate. This disrupted differentiation results from a transient state of sex ambiguity in pre-supporting cells, which is later resolved towards the ovarian fate. Consistent with known mechanisms of miRNA-mediated gene regulation, the expression of miR-17[~]92 target genes is not stabilized in undifferentiated XY mutant gonads, affecting concomitantly the fine regulation of gene networks with critical roles in developing gonads. Our results demonstrate that microRNAs are key components for mammalian sex determination, controlling the timing of Sry expression and Sertoli cell differentiation.

developmental biology↗

bioRxiv2022

Cell adhesion and immune response, two main functions altered in the transcriptome of seasonally regressed testes of two mammalian species

In species with seasonal breeding, male specimens undergo substantial testicular regression during the non-breeding period of the year. However, the molecular mechanisms that control this biological process are largely unknown. Here, we report a transcriptomic analysis on the Iberian mole, Talpa occidentalis, in which the desquamation of live, non-apoptotic germ cells is the major cellular event responsible for testis regression. By comparing testes at different reproductive states (active, regressing and inactive), we demonstrate that the molecular pathways controlling the cell adhesion function in the seminiferous epithelium, such as the MAPK, ERK and TGF-{beta} signalling, are altered during the regression process. In addition, inactive testes display a global upregulation of genes associated with immune response, indicating a selective loss of the "immune privilege" that normally operates in sexually active testes. Interspecies comparative analyses using analogous data from the Mediterranean pine vole, a rodent species where testis regression is controlled by halting meiosis entry, revealed a common gene expression signature in the regressed testes of these two evolutionary distant species. Our study advances in the knowledge of the molecular mechanisms associated to gonadal seasonal breeding, highlighting the existence of a conserved transcriptional program of testis involution across mammalian clades. Research HighlightsBy comparing the trascriptomes of the testes from males of the iberian mole, Talpa occidentalis (order Eulipotyphla), captured at different stages of the seasonal breeding cycle of this species, we show that two main functions are altered during seasonal testis regression: cell adhesion and immune response. The fact that the same functions alre also altered in the Mediterranean pine vole, Microtus duodecimcostatus (order Rodentia), evidences the existence of a conserved transcriptional program of testis regression across mammalian clades.

molecular biology↗