Biology subjects

ZHOU, X.

Publications and source records attributed to ZHOU, X..

4 recordsLinked to original sources

bioRxiv2025

Functional Landscape of Zebrafish Gonadotropins and Receptors: A Comprehensive Genetic Analysis

In vertebrates, reproduction is controlled by two master hormones, or gonadotropins, from the pituitary: follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which act through their cognate receptors, FSHR and LHCGR, in gonads. Like other vertebrates, zebrafish also has two gonadotropins and respective receptors. However, while zebrafish FSH activates Fshr specifically, its LH can activate both Fshr and Lhcgr, suggesting three signaling pathways - the canonical FSH-Fshr and LH-Lhcgr pathways, and a non-canonical LH-Fshr pathway. To dissect functional roles of these pathways, we generated a series of zebrafish mutants lacking one to all four genes encoding the two ligands and their receptors: fshb, lhb, fshr, and lhcgr. Single mutants confirmed the essential roles of FSH and LH in zebrafish reproduction. Double mutants demonstrated the functionality of all three pathways, especially the non-canonical LH-Fshr pathway, and highlighted the importance of Fshr in mediating both FSH and LH actions. Transcriptome analysis of double mutant follicles (infertile lhb-/-;lhcgr-/- with FSH-Fshr and fertile fshb-/-;lhcgr-/- with LH-Fshr) revealed potential molecular mechanisms underlying LH stimulation of oocyte maturation and ovulation via Fshr. Triple mutants revealed spontaneous, ligand-independent activities of Fshr and Lhcgr, in supporting spermatogenesis. Males with only fshb or lhb were infertile, with testes dominated by spermatogonia and spermatocytes with few spermatozoa. The quadruple mutant (fshb-/-;lhb-/-;fshr-/-;lhcgr-/-) displayed an all-male phenotype with underdeveloped, infertile gonads primarily containing spermatogonia, suggesting a critical role for gonadotropins in sex differentiation and gonadal development. This comprehensive genetic study provides insights into functional importance of gonadotropins in zebrafish reproduction and their signaling mechanisms. Author summaryFollicle-stimulating hormone (FSH) and luteinizing hormone (LH) are two key hormones regulating vertebrate reproduction via their specific receptors, FSHR and LHCGR. Zebrafish, like other vertebrates, also has two hormones and two receptors. Interestingly, zebrafish LH signals not only through its cognate receptor Lhcgr but also through FSH receptor Fshr, suggesting existence of three signaling pathways (FSH-Fshr, LH-Fshr and LH-Lhcgr). To investigate the functionality of these pathways, we created various zebrafish mutant lines with all mutational combinations for these hormones and receptors. Our findings demonstrated that Fshr, when activated by either FSH or LH, played a critical role in ovarian growth and folliculogenesis. LH was necessary for oocyte maturation and ovulation, and the LH-Fshr pathway alone was adequate to support the entire process of female reproduction. All three pathways were sufficient to sustain male reproductive function. We further observed that the receptors exhibited low-level spontaneous activities in the absence of hormones, that could support spermatogenesis. Fish lacking all four genes developed only as males with extremely underdeveloped, non-functional testes. This highlights critical roles for gonadotropins not only in fertility, but also in sex differentiation. Our work provides comparative insights into the fundamental mechanisms by which gonadotropins control reproductive processes in vertebrates.

genetics↗

bioRxiv2025

Remote Control of Cell Signaling through Caveolae Mechanics

Caveolae are invaginated plasma membrane nanodomains traditionally associated with membrane trafficking and signaling. These multifunctional organelles are also essential mechanosensors mediating the cell response to mechanical stress. We investigated the role of caveolae mechanics in regulating various signaling pathways. Single molecule imaging and super resolution microscopy revealed that mechanical stress rapidly triggers caveolae disassembly and the release of caveolin-1 scaffolds, which exhibit enhanced diffusion at the plasma membrane. This promoted direct interaction between the caveolin-1 scaffolding domain and the tyrosine kinase JAK1, leading to the inhibition of its catalytic activity. A similar process was observed for eNOS, PTEN, and PTP1B. Remote control of signaling by caveolae was validated by a theoretical model based on caveolae thermodynamics. These findings establish a novel mechanotransduction paradigm where signaling information is decoded remotely from the initial mechanosensing caveola, through dynamic and reversible assembly of tension-controlled complexes between signaling effectors and caveolin-1 scaffolds.

cell biology↗

bioRxiv2024

Prediction and principle discovery of drug combination based on multimodal friendship features

Combination therapy, which can improve therapeutic efficacy and reduce side effects, plays an important role in the treatment of multiple complex diseases. Yet, the design principles of molecular combinations remain unclear. In addition, the huge search space of candidate drug combinations and the numerous heterogeneous data has brought us a big challenge. Here, we proposed a Friendship based Method (FSM), which integrates diverse drug-to-drug information to predict drug combinations for specific diseases. By quantifying the friendship-based relationship between drugs, we found that there is a moderate similarity between the drugs of effective drug combinations in a high-dimensional, heterogeneous feature space. Following this discovery, FSM applied a two-step strategy to predict clinically efficacious drug combinations for specific diseases. First, our method employs the friendship features to evaluate whether each drug is combinable. Then, the synergistic potential of combinable drugs was further evaluated. FSM was validated on two types of disease. The results show that FSM achieves substantial performance improvement over other state-of-the-art methods and tends to have low toxicity. These results indicate that our model could potentially offer a generic, powerful strategy to identify efficacious combination therapies in the vast search space.

systems biology↗

bioRxiv2023

Highly sensitive spatial transcriptomics using FISHnCHIPs of multiple co-expressed genes

High-dimensional, spatially resolved analysis of intact tissue samples promises to transform biomedical research and diagnostics, but existing spatial omics technologies are costly and labor-intensive. We present FISHnCHIPs for highly sensitive in situ profiling of cell types and gene expression programs. FISHnCHIPs achieves this by simultaneously imaging [~]2-35 co-expressed genes that are spatially co-localized in tissues, resulting in similar spatial information as single-gene FISH, but at [~]2-20-fold higher sensitivity. Using FISHnCHIPs, we imaged up to 53 gene modules from the mouse kidney and mouse brain, and demonstrated high-speed, large field-of-view profiling of a whole tissue section. FISHnCHIPS also revealed spatially restricted localizations of cancer-associated fibroblasts in a human colorectal cancer biopsy. Overall, FISHnCHIPs enables robust and scalable spatial transcriptomics analysis of tissues with normal physiology or undergoing pathogenesis.

genomics↗