Biology subjects

Menendez, J.

Publications and source records attributed to Menendez, J..

4 recordsLinked to original sources

bioRxiv2024

Plxnd1-mediated mechanosensing of blood flow controls the caliber of the Dorsal Aorta via the transcription factor Klf2

The cardiovascular system generates and responds to mechanical forces. The heartbeat pumps blood through a network of vascular tubes, which adjust their caliber in response to the hemodynamic environment. However, how endothelial cells in the developing vascular system integrate inputs from circulatory forces into signaling pathways to define vessel caliber is poorly understood. Using vertebrate embryos and in vitro-assembled microvascular networks of human endothelial cells as models, flow and genetic manipulations, and custom software, we reveal that Plexin-D1, an endothelial Semaphorin receptor critical for angiogenic guidance, employs its mechanosensing activity to serve as a crucial positive regulator of the Dorsal Aortas (DA) caliber. We also uncover that the flow-responsive transcription factor KLF2 acts as a paramount mechanosensitive effector of Plexin-D1 that enlarges endothelial cells to widen the vessel. These findings illuminate the molecular and cellular mechanisms orchestrating the interplay between cardiovascular development and hemodynamic forces. HighlightsO_LIPlexin-D1 mechanosensing of blood flow tunes the caliber of the Dorsal Aorta (DA) C_LIO_LIThe DA widens without raising endothelial cell numbers, which can change separate from the caliber C_LIO_LIThe Kruppel-like transcription factor 2 (KLF2) is a key Plexin-D1 mechano-effector during development C_LIO_LIKLF2 increases endothelial cell size to expand the DA caliber C_LI

developmental biology↗

bioRxiv2023

Nuclear VANGL2 Inhibits Lactogenic Differentiation

Planar cell polarity (PCP) proteins coordinate tissue morphogenesis by governing cell patterning and polarity. Asymmetrically localized on the plasma membrane of cells, PCP proteins are also trafficked by endocytosis, suggesting they may have intracellular functions that are dependent or independent of their extracellular role, but whether these functions extend to transcriptional control remains unknown. Here, we show the nuclear localization of transmembrane, PCP protein, VANGL2, in undifferentiated, but not differentiated, HC11 cells, which serve as a model for mammary lactogenic differentiation. Loss of Vangl2 function results in upregulation of pathways related to STAT5 signaling. We identify DNA binding sites and a nuclear localization signal in VANGL2, and use CUT&RUN to demonstrate direct binding of VANGL2 to specific DNA binding motifs, including one in the Stat5a promoter. Knockdown (KD) of Vangl2 in HC11 cells and primary mammary organoids results in upregulation of Stat5a, Ccnd1 and Csn2, larger acini and organoids, and precocious differentiation; phenotypes rescued by overexpression of Vangl2, but not Vangl2{Delta}NLS. Together, these results advance a paradigm whereby PCP proteins coordinate tissue morphogenesis by keeping transcriptional programs governing differentiation in check.

cell biology↗

bioRxiv2023

Transcriptomic response in pyroxsulam-resistant and susceptible Bromus sterilis identified three distinct mechanisms of resistance

Bromus sterilis has evolved into a more predominant weed in the Czech Republics winter wheat fields, owing largely to the widespread application of pyroxsulam for its management. In this study, we report a biotype that has developed resistance to pyroxsulam and has also shown cross- resistance to other herbicides. Although no differences in ploidy levels or no mutations of acetolactate synthase (ALS) were detected, a significant elevation of ALS enzyme activity was observed in the R biotype. Through combined analysis of enzyme inhibition and total transcript expression (RNA-Seq), we have identified differentially expressed transcripts that potentially contribute to pyroxsulam metabolism. Furthermore, we observed a significant increase in the expression of genes involved in redox mechanisms and transporters that could contribute to enhanced resistance to pyroxulam in the R biotype. Our results present a novel understanding of herbicide resistance in B. sterilis through three distinct resistance mechanisms (ALS gene overexpression, enhanced metabolism and reduced translocation) without mutation in the herbicide target protein. This understanding is the foundation for improving management strategies for herbicide resistant B. sterilis.

plant biology↗

bioRxiv2022

Subfunctionalized expression drives evolutionary retention of ribosomal protein paralogs in vertebrates

The formation of paralogs through gene duplication is a core evolutionary process. For paralogs that encode components of protein complexes such as the ribosome, a central question is whether they encode functionally distinct proteins, or whether they exist to maintain appropriate total expression of equivalent proteins. Here, we systematically tested evolutionary models of paralog function using the mammalian ribosomal protein paralogs eS27 (Rps27) and eS27L (Rps27l) as a case study. We first showed that eS27 and eS27L have inversely correlated mRNA abundance across cell types, with the highest eS27 in lymphocytes and the highest eS27L in mammary alveolar cells and hepatocytes. By endogenously tagging the eS27 and eS27L proteins, we demonstrated that eS27- and eS27L- ribosomes associate preferentially with different transcripts. Furthermore, we generated murine eS27 and eS27L loss-of-function alleles that are homozygous lethal at different developmental stages. However, strikingly, we found that expressing eS27 protein from the endogenous eS27L locus, or vice versa, completely rescues loss-of-function lethality and yields mice with no detectable deficits. Together, these findings suggest that eS27 and eS27L are evolutionarily retained because their subfunctionalized expression patterns render both genes necessary to achieve the requisite total expression of two equivalent proteins across cell types. Our work represents the most in-depth characterization of a mammalian ribosomal protein paralog to date and highlights the importance of considering both protein function and expression when investigating paralogs.

genetics↗