Biology subjects

Knox, S.

Publications and source records attributed to Knox, S..

5 recordsLinked to original sources

bioRxiv2026

Gene Expansion and Regulatory Rewiring Shape Sex-Biased Evolution of the Mouse Submandibular Gland Secretome

Background Mammalian saliva plays essential roles in digestion, immunity, and host-microbiome interactions, yet its protein composition varies widely across species and sexes. This diversity makes saliva a powerful model to study evolution of gene expression. Here, we compared mouse and human salivary glands at the genomic, transcriptomic, and proteomic levels to understand how saliva composition evolves. Results We found that evolution of gene expression in mouse salivary glands is driven by rapid gene turnover and sexual dimorphism. In the submandibular and sublingual glands, 68% and 73% of expression from genes encoding secreted proteins derives from lineage-specific genes that lack one-to-one human orthologs. This contrasts the prevailing view that gene expression is largely conserved across tissues and highlights saliva as an unusually dynamic system of molecular evolution. Mouse submandibular gland shows striking sexual dimorphism, with 1537 tissue specific sex-biased genes, 3.8 times higher than in the liver (p<0.001), a classic model of sex-biased expression. We also identified sex-specific expression of glycosylation genes associated with differential Muc19 sialylation. These results suggest that sexual dimorphism in mouse saliva arises from both transcriptional differences in secreted proteins and sex-specific post-translational modifications. Further, differentially expressed genes in submandibular gland cluster in genomic regions shaped by recent gene duplication, such as the kallikrein gene cluster, a mouse-specific expansion that accounts for ~16.4% of male-biased submandibular gland expression. Our analyses suggest that this bias arises through regulatory changes that are expanded by gene duplication, including the spread of a testosterone-associated regulatory motif and the expansion of a shared chromatin domain that promotes coordinated gene regulation. Conclusions Together, our results reveal that lineage-specific genes disproportionately shape the mouse salivary transcriptome and that gene duplication and regulatory rewiring contribute to the rapid evolution of sex-biased expression in the submandibular gland. We describe a novel mechanism through which lineage-specific gene duplication and regulatory rewiring drive rapid, sex-specific evolution of the mammalian saliva. Our findings support saliva as an evolutionarily dynamic system and are consistent with developmental systems drift, whereby similar phenotypes across species may be maintained despite substantial divergence in their underlying gene-regulatory programs.

evolutionary biology↗

bioRxiv2025

Chronic degenerative failure of salivary glands can be reversed through restoring mitochondrial function

Chronic degenerative wounds are often deemed irreparable, directing research efforts to focus predominantly on acute tissue injury regeneration while leaving endogenous repair mechanisms for chronically damaged tissues largely unexplored. In this study, we demonstrate that non-healing, severely degenerated salivary gland tissues can be fundamentally restored through first-line treatment with muscarinic agonists. This approach rescues tissue structure and function, returning it to a homeostatic-like state, and reactivates endogenous regeneration processes to drive new cell expansion that persists for months post-treatment. Furthermore, neuromimetic activation profoundly depletes radiation-induced DNA damage and re-establishes the nerve-acinar relationship, ultimately restoring the tissues physiological capacity to maintain homeostasis, even in the absence of treatment. We show that full recovery of organ function, comparable to uninjured controls, is primarily mediated by the re-differentiation of aberrantly de-differentiated epithelial acinar cells and the restoration of mitochondrial function via a muscarinic-calcium signaling pathway. These findings challenge the prevailing notion that chronic organ degeneration is irreversible and propose a readily testable therapeutic strategy for epithelial restoration with potential applications across a spectrum of chronic injuries.

cell biology↗

bioRxiv2024

Rebuilding the autoimmune-damaged corneal stroma through topical lubrication

Corneal lubrication is the most common treatment for relieving the signs and symptoms of dry eye and is considered to be largely palliative with no regenerative functions. Here we challenge this notion by demonstrating that wetting the desiccated cornea of an aqueous-deficient mouse model with the simplest form of lubrication, a saline-based solution, is sufficient to rescue the severely disrupted collagen-rich architecture of the stroma, the largest corneal compartment that is essential to transparency and vision. At the single cell level we show that stromal keratocytes responsible for maintaining stromal integrity are converted from an inflammatory state into unique reparative cell states by lubrication alone, thus revealing the extensive plasticity of these cells and the regenerative function of lubricating the surface. We further show that the generation of a reparative phenotype is due, in part, to disruption of an IL1{beta} autocrine amplification loop promoting chronic inflammation. Thus, our study uncovers the regenerative potential of topical lubrication in dry eye and represents a paradigm shift in our understanding of its therapeutic impact.

immunology↗

bioRxiv2021

Aldehyde dehydrogenase 3A1 deficiency leads to mitochondrial dysfunction and impacts salivary gland stem cell self-renewal, differentiation and survival

Adult salivary stem/progenitor cells (SSPC) have an intrinsic property to self-renew in order to maintain tissue architecture and homeostasis. Adult salivary glands have been documented to harbor SSPC, which have been shown to play a vital role in the regeneration of the glandular structures post radiation damage. We have previously demonstrated that activation of aldehyde dehydrogenase 3A1 (ALDH3A1) after radiation reduced aldehyde accumulation in SSPC, leading to less apoptosis and improved salivary function. We subsequently found that sustained pharmacological ALDH3A1 activation is critical to enhance regeneration of murine submandibular gland after radiation damage. Further investigation shows that ALDH3A1 function is crucial for SSPC self-renewal and differentiation even in the absence of radiation stress. Salivary glands from Aldh3a1-null mice have fewer acinar structures than wildtype mice. ALDH3A1 deletion or pharmacological inhibition in SSPC leads to a decrease in mitochondrial DNA copy number, lower expression of mitochondrial specific genes and proteins, structural abnormalities, lower membrane potential, and reduced cellular respiration. Loss or inhibition of ALDH3A1 also elevates ROS levels and accumulation of ALDH3A1 substrate 4-hydroxynonenal (4-HNE, a lipid peroxidation product), leading to decreased survival of murine SSPC that can be rescued by treatment with 4-HNE specific carbonyl scavengers. Our data indicate that ALDH3A1 activity protects mitochondrial function and is important for the development and regeneration activity of SSPC. This knowledge will help to guide our translational strategy of applying ALDH3A1 activators in the clinic to prevent radiation-related hyposalivation in head and neck cancer patients.

cell biology↗

bioRxiv2019

Development of mouse and human cochlea at single cell resolution

Hearing loss is a common and disabling condition, yet our understanding of the physiologic workings of the inner ear has been limited by longstanding difficulty characterizing the function and characteristics of the many diverse, fragile, and rare cell types in the cochlea. Using single-cell RNA-sequencing and a novel clustering algorithm, CellFindR, we created a developmental map of the mouse and human cochlea, identifying multiple previously undescribed cell types, progenitor populations, and predicted lineage relationships. We additionally associated the expression of known hearing loss genes to the cell types and developmental timepoints in which they are expressed. This work will serve as a resource for understanding the molecular basis of hearing and designing therapeutic approaches for hearing restoration.

bioinformatics↗