Biology subjects

Mendez-Martinez, L.

Publications and source records attributed to Mendez-Martinez, L..

3 recordsLinked to original sources

bioRxiv2025

Genetic ablation of Pth4 disrupts calcium-phosphate balance, bone development, and kidney transcriptome in teleosts

Parathyroid hormone 4 (Pth4) is an evolutionarily conserved member of the PTH family, expressed in hypothalamic neurons and lost in eutherian mammals. In order to elucidate its role in mineral homeostasis and skeletal development, a pth4 knockout (pth4KO) zebrafish line was generated using CRISPR/Cas9 and transcriptomic profiling was conducted across six key tissues: brain, kidney, intestine, gills, scales, and bone. The results obtained demonstrated that the loss of Pth4 led to pronounced disturbances in calcium and phosphate homeostasis, skeletal deformities, and widespread tissue-specific transcriptional alterations. Notably, dysregulation of mineral regulatory genes-- such as fgf23, phex, and slc34a1a was particularly evident in the kidney, suggesting disruption of the FGF23-Klotho axis. In parallel, differential expression of extracellular matrix genes (col1a1a, col10a1a, col11a1) and matrix remodeling enzymes (mmp9, mmp13a, mmp2) in bone and scales indicated impaired skeletal remodeling. Together, these findings highlight a pivotal role for Pth4 in the endocrine and local regulation of mineral metabolism and skeletal integrity, expanding our understanding of PTH family functions in vertebrate physiology.

developmental biology↗

bioRxiv2025

alms1 regulates the immune response and brain ageing in zebrafish

The ALMS1 gene plays a crucial role in maintaining cellular homeostasis through its involvement in primary cilium assembly, cytoskeletal regulation, and signalling pathways such as NOTCH and TGF-{beta}. Pathogenic variants in ALMS1 are associated with Alstrom Syndrome (ALMS), a multi-systemic ciliopathy characterised by neurosensory deficits, metabolic disorders, and multi-organ fibrosis. To better understand the tissue-dependent role of ALMS1, we utilised CRISPR/Cas9 technology to develop a zebrafish model with alms1 depletion. Multi-tissue transcriptomic profiling revealed that alms1 depletion has pleiotropic effects on gene expression, with the brain and eyes displaying the most pronounced transcriptomic alterations, including disrupted ciliary function and immune dysregulation. Inflammatory and innate immune pathways along with glutamatergic synapse-related processes were significantly affected in the brain and eyes but with different gene expression signatures. The analysis further highlights tissue-specific processes, primarily associated with organ dysfunction. Additionally, our findings underscore the role of alms1 in regulating age-associated gene expression profiles in the brain, suggesting a link between ciliary dysfunction and accelerated brain ageing. Comparative analyses with Bardet-Biedl Syndrome iPSC models revealed shared pathways, reinforcing the potential of ciliopathies as models for ageing-related disorders. This study provides novel insights into the tissue-specific functions of alms1 and the molecular mechanisms underlying ALMS, paving the way for the development of targeted therapeutic strategies.

genomics↗

bioRxiv2021

Common variation in EDN1 regulatory regions highlights the role of PPARγ as a key regulator of Endothelin in vitro

Pulmonary Arterial Hypertension (PAH) is a rare disease caused by the obliteration of the pulmonary arterioles, increasing pulmonary vascular resistance and eventually causing right heart failure. Endothelin-1 is a vasoconstrictor peptide whose levels are indicators of disease progression and its pathway is one of the commonest targeted by current treatments. We sequenced the EDN1 untranslated regions of a small subset of PAH patients, predicted the effect in silico, and used a luciferase assay with the different genotypes to analyze its influence on gene expression. Finally, we used siRNAs against the major transcription factors predicted for these regions (PPAR{gamma}, KLF4, and VDR) to assess Endothelin-1 expression in cell culture and validate the binding sites. First, we detected a SNP in the 5UTR (rs397751713) and another in the 3regulatory region (rs2859338) that increased luciferase activity in vitro depending on their genotype. We determined in silico that KLF4/PPAR{gamma} could be binding in the rs397751713 and VDR in rs2859338. By using siRNAs and luciferase, we determined that PPAR{gamma} binds differentially in rs397751713. PPAR{gamma} and VDR Knock-Down, increased EDN1 mRNA levels and Endothelin-1 production in PAECs, while PPAR{gamma} and KLF4 Knock-Down increased the Endothelin-1 production in HeLa. In conclusion, common variants in EDN1 regulatory regions could alter Endothelin-1 levels. We were able to validate that PPAR{gamma} binds in rs397751713 and is key to regulate Endothelin-1. Also, KLF4 and VDR regulate Endothelin-1 production in a cell-dependent manner, but for VDR this interaction does not happen by binding directly to the regions we studied.

cell biology↗