Biology subjects

Segarra, M.

Publications and source records attributed to Segarra, M..

3 recordsLinked to original sources

bioRxiv2026

Vascular signals coordinate cerebellar circuitry development

Neural circuit assembly requires precise coordinated interactions between developing neurons and the vasculature, yet the instructive signals provided by endothelial cells remain largely unknown. Here, we identify a vascular-to-neural signaling axis that orchestrates postnatal cerebellar development. Endothelial-specific deletion of the adaptor protein Dab1 in mice disrupted vascular patterning and uncoupled the growth of major cerebellar neuronal populations. We show that endothelial Dab1 in the cerebellum drives secretion of the morphogen Wnt5a, which acts through Frizzled-2 to restrain granule-cell progenitor proliferation and promote Purkinje-cell dendritic maturation. Endothelial Wnt5a deletion phenocopied Dab1 endothelial mutant (Dab1i{Delta}EC) defects, whereas exogenous Wnt5a restored normal progenitor dynamics in Dab1i{Delta}EC cerebellar slices, demonstrating pathway sufficiency. Functionally, loss of this vascular signal impaired Purkinje-cell firing, diminished parallel-fiber input, reduced synapse formation from both parallel and climbing fibers, and disrupted long-term plasticity. These findings reveal a key instructive role for blood vessels in shaping cerebellar architecture and establishing functional circuit connectivity.

neuroscience↗

bioRxiv2025

A microprotein encoded by FERMT3 modulates endothelial cell protein catabolism and induces p53-mediated cell cycle arrest and senescence

BackgroundHuman endothelial cells express numerous microproteins (miPs) encoded by small open reading frames (smORFs) distributed throughout the genome, yet the biological functions of most remain unknown. This study set out to characterize a novel 69 amino acid miP encoded by a smORF located within the coding sequence of the FERM domain containing kindlin-3 transcript (miP-FERMT3). MethodsConfocal microscopy was used to determine the subcellular localization of miP-FERMT3 in endothelial cells and its interaction partners were determined by mass spectrometry and immunoblotting. RNA sequencing identified transcriptional alterations induced by miP-FERMT3 overexpression. Cell proliferation and cell cycle stages were assessed by live cell imaging, EdU incorporation and flow cytometry, while senescence was examined by senescence-associated {beta}-galactosidase staining, live cell imaging and RT-qPCR-based measurement of telomere length. ResultsIn endothelial cells miP-FERMT3 localized mainly to centriole subdistal appendages, where it interacted with proteins involved in ubiquitin- and proteasome-dependent protein catabolism, including PSMD9, CUL2 and TRIM8. Consistent with these interactions, cells expressing miP-FERMT3 exhibited increased global protein ubiquitination, enhanced centrosomal neddylation and elevated proteasomal activity. MiP-FERMT3 also promoted the nuclear accumulation of p53, which subsequently repressed FOXM1 expression, leading to the downregulation of genes required for cell-cycle progression and upregulation of genes involved in cell cycle inhibition, resulting in cell-cycle arrest. Cells expressing the miP also demonstrated multiple hallmarks of cellular senescence, including enlarged size, DNA damage, increased senescence-associated {beta}-galactosidase activity, telomere shortening and paracrine pro-inflammatory activation of naive endothelial cells. Analyses of independent murine and human transcriptomic and proteomic aging datasets further revealed that FERMT3 expression and protein abundance increase with age. ConclusionsThese findings identify miP-FERMT3 as a novel regulator of protein catabolism and p53-dependent cell cycle arrest and cellular senescence in endothelial cells. Given the aging-associated upregulation of FERMT3 in mouse and human endothelial cells, increased miP-FERMT3 expression may contribute to the onset of vascular senescence as a hallmark of aging.

cell biology↗

bioRxiv2024

Vascular FLRT2 regulates venous-mediated angiogenic expansion and CNS barriergenesis

Veins have emerged as the origin of all other endothelial cell subtypes needed to expand vascular networks during developmental and pathological neoangiogenesis. Here, we uncover the significant role of the angioneurin Fibronectin Leucine Rich Transmembrane protein (FLRT) 2 in central nervous system (CNS) vascular development in the mouse. Early postnatal FLRT2 deletion reveals specific defects in retinal veins, impacting endothelial cell proliferation, sprouting and polarity that result in reduced tip cells at the vascular front. FLRT2 interacts with VE-cadherin and together with the endocytic adaptor protein Numb contribute to the modulation of adherens junction morphology in both retina and cerebral cortex in vivo. Utilizing expansion microscopy, we visualize the altered dynamic distribution of VE-cadherin in tissue of FLRT2 endothelial mutants. Additionally, FLRT2 in cortical vessels regulates the crosstalk between adherens and tight junctions, influencing blood-brain barrier development. Our findings position FLRT2 as a vein-specific crucial regulator of CNS vascular development.

neuroscience↗