Biology subjects

Olson, L. E.

Publications and source records attributed to Olson, L. E..

9 recordsLinked to original sources

bioRxiv2026

Constitutive PDGFRb activation drives connective tissue overgrowth through STAT5-IGF1 signaling

Autosomal dominant gain-of-function mutations in platelet-derived growth factor receptor beta (PDGFRb) cause overgrowth of the skeleton and other connective tissue in Kosaki overgrowth syndrome. However, the target cell type and signaling pathways underlying PDGFRb-driven overgrowth are unknown. Normal postnatal growth is controlled by pituitary-secreted growth hormone (GH), which activates the STAT5 transcriptional factor to upregulate insulin-like growth factor 1 (IGF1). To investigate the role of the GH-STAT5-IGF1 pathway in PDGFRb-related overgrowth, we generated mice with a PDGFRb gain-of-function mutation in skeletal and fibroblast lineages, which resulted in STAT5 activation and gigantism. Conditional deletion of Stat5ab in connective tissue lineages rescued skeletal overgrowth and keloid-like fibrosis in the skin. Conditional deletion of GH receptor (Ghr) did not rescue overgrowth, indicating the physiological activator of STAT5 is not required for overgrowth. However, deletion of Igf1, the STAT5 target gene, and its receptor, Igf1r, in connective tissue, rescued the overgrowth phenotype. These findings demonstrate a GHR-independent STAT5-IGF1 signaling pathway in mutant connective tissue cells, which mediates PDGFRb-driven overgrowth in mice and potentially in humans with similar PDGFRB mutations.

genetics↗

bioRxiv2026

Connective tissue growth in a mouse model of Kosaki overgrowth syndrome is limited by STAT1

Mutations in platelet-derived growth factor receptor beta (PDGFR{beta}) cause Kosaki overgrowth syndrome (KOGS). Patients exhibit increased linear growth, craniosynostosis, and thin skin with increased elasticity and scarring. Of the KOGS patients identified to date, three unrelated individuals carried a P584R mutation in the juxtamembrane domain of PDGFR{beta}, resulting in constitutive receptor activation. Due to the limited number of patients, extensive phenotyping and exploration of the molecular basis of disease, including modifier genes, has not been completed. We generated conditional knock-in mice to express mouse PDGFR{beta} with a P583R mutation, corresponding to human P584R, under control of the endogenous Pdgfrb gene. Mutant mice were born at the expected ratio and appeared normal at birth. At 3 weeks of age, mutants began to exhibit connective tissue changes: increased body weight and bone length, craniosynostosis, ectopic bone in the tail and tendons, thin lipodystrophic skin, and high incidence of penile and rectal prolapse. To identify signaling changes caused by mutant PDGFR{beta} signaling, we performed western blotting and phosphoproteomics on dermal fibroblasts. This uncovered increased phosphorylation of PDGFR{beta}, PLC{gamma}, Akt1, Shp2, STAT1, STAT2, STAT3, and STAT5. Analysis of 6,621 proteins and 5,386 phosphopeptides identified upregulation of interferon signaling genes linked to STAT1. In many cell types, STAT1 has tumor-suppressor functions and acts to inhibit cell cycle. We generated Stat1-/- Pdgfrb+/P583R mice to test the contribution of STAT1 to KOGS phenotypes. Stat1-deletion exacerbated overgrowth and calvaria dysmorphogensis, and caused keloid-like skin fibrosis. No phenotypes present in the original Pdgfrb+/P583R mice were reverted to normal after Stat1 deletion. Therefore, the P583R mouse model mirrored KOGS phenotypes and increased activation of multiple PDGFR{beta} signaling mediators; in this context, STAT1 activity opposes PDGFR{beta}-driven overgrowth and fibrosis.

developmental biology↗

bioRxiv2026

Historic and contemporary museum specimens implicate Northern Red-backed Vole (Clethrionomys rutilus) as borealpox host as early as 1990s

Borealpox virus (BRPV; formerly Alaskapox) is an orthopoxvirus that has caused seven reported human infections in Alaska since 2015, including a fatal case in 2023. The natural reservoir of BRPV is unknown, although previous investigations have raised the possibility of wild small mammals transmitting the virus to humans, either through direct contact or via domestic cats and dogs. To understand which species may be involved in the maintenance and/or spillover of BRPV in Alaska, we trapped and sampled wild small mammals (including voles, shrews, and squirrels) in 2021 and 2024 near reported human case locations in Fairbanks and the Kenai Peninsula, respectively. We found evidence of previous exposure to orthopoxviruses in five species (including the House Mouse, Mus musculus) and detected BRPV DNA as well as viable virus in Northern Red-backed Voles (Clethrionomys rutilus). Further, screening of tissues from historical museum specimens revealed BRPV DNA in C. rutilus specimens collected in Denali National Park and Preserve in 1998 and 1999, 17 years before the first reported human case of BRPV. Phylogenomic analysis of all human and animal BRPV isolates strongly supports the hypothesis of local human infections through multiple spillover events. These findings suggest C. rutilus as a possible reservoir species for BRPV and indicate that BRPV has been present in Alaskan wild small-mammal populations for at least 25 years. Our study highlights the potential of museum collections to elucidate the temporal, spatial, and host ranges of emerging pathogens. Further museum- and field-based sampling will clarify the true geographic range of BRPV, which is closely related to Old World orthopoxviruses and may be circulating beyond North America.

ecology↗

bioRxiv2026

Overactive PDGFRα and PDGFRβ promote distinct yet overlapping phenotypes of skeletal muscle fibrosis and stiffness, with PDGFRβ also driving drastic muscle growth

Background: Fibrosis accumulates in skeletal muscle over time and leads to greater muscle rigidity, stiffness, and increased risk of injuries. However, investigations of experimental models to study the mechanisms through which muscle fibrosis occurs are often confounded by injury or disease. The contribution of platelet-derived growth factor receptors alpha and beta (PDGFR or PDGFR{beta}) to muscle fibrosis is yet to be clarified. We hypothesized that both receptors would promote ECM deposition and fibrosis, causing muscle stiffening and weakness, with sex-specific differences arising due to hormonal influences on receptors. Methods: To test this hypothesis, we used a mouse model with inducible overactive PDGFR or PDGFR{beta} signaling and assessed various indicators of muscle function, metabolism, motor coordination, exercise capacity, collagen deposition, and muscle stiffness. Results: Overactive PDGFR led to more collagen deposition, increased collagen crosslinking, and higher AGE/LOX protein levels, all of which correlated with greater muscle stiffness compared to CON. Overactive PDGFR{beta} resulted in greater muscle mass and lower fat mass, and had higher collagen deposition in female mice compared to CON. There were also sex-specific differences with fibrotic remodeling, muscle stiffness, and muscle size in response to overactive PDGFR and PDGFR{beta} signaling. Conclusion: These findings establish PDGFR and PDGFR{beta} signaling as distinct regulators of muscle remodeling and establish overactive PDGFR as a mouse model to study skeletal muscle fibrosis in the absence of other confounding variables.

physiology↗

bioRxiv2025

Mouse scalp development requires Rac1 and SRF for the maintenance of mechanosensing mesenchyme

Regulation of essential cellular responses like proliferation, migration, and differentiation is crucial for normal development. Rac1, a ubiquitously expressed small GTPase, executes these responses under the regulation of guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GTPases). Mutations in specific GEFs (DOCK6) and GTPases (AHGAP31) that regulate Rac1 are associated with Adams-Oliver syndrome (AOS), a developmental syndrome characterized by congenital scalp defects and limb truncations. Genetic ablation of Rac1 in the mouse embryonic limb ectoderm results in limb truncation. However, the etiology of Rac1-associated cranial defects is unknown. To investigate the origin and nature of cranial defects, we used a mesenchymal Cre line (Pdgfra-Cre) to delete Rac1 in cranial mesenchyme. Rac1-KO mice died perinatally and lacked the apical portion of the calvarium and overlying dermis, resembling cranial defects seen in severe cases of AOS. In control embryos, -smooth muscle actin (SMA) expression was spatially restricted to the apical mesenchyme, suggesting a mechanical interaction between the growing brain and the overlying mesenchyme. In Rac1-KO embryos there was reduced proliferation of apical mesenchyme, and reduced expression of SMA and its regulator, serum response factor (SRF). Remarkably, Srf-KO mice generated with Pdgfra-Cre recapitulated the cranial phenotype observed in Rac1-KO mice. Together, these data suggest a model where Rac1 and SRF are critical to maintaining apical fibroblasts in a mechano-sensitive and proliferative state needed to complete cranial development.

developmental biology↗

bioRxiv2023

Arctos: Community-driven innovations for managing biodiversity and cultural collections

Museum collections house millions of objects and associated data records that document biological and cultural diversity. In recent decades, digitization efforts have greatly increased accessibility to these data, thereby revolutionizing interdisciplinary studies in evolutionary biology, biogeography, epidemiology, cultural change, and human-mediated environmental impacts. Curators and collection managers can make museum data as accessible as possible to scientists and learners by using a collection management system. However, selecting a system can be a challenging task. Here, we describe Arctos, a community solution for managing and accessing collections data for research and education. Specific goals are to: (1) Describe the core elements of Arctos for a broad audience with respect to the biodiversity informatics principles that enable high quality research; (2) Highlight the unique aspects of Arctos; (3) Illustrate Arctos as a model for supporting and enhancing the Digital Extended Specimen; and (4) Emphasize the role of the Arctos community for improving data discovery and enabling cross-disciplinary, integrative studies within a sustainable governance model. In addition to detailing Arctos as both a community of museum professionals and a collection database platform, we discuss how Arctos achieves its richly annotated data by creating a web of knowledge with deep connections between catalog records and derived or associated data. We also highlight the value of Arctos as an educational resource. Finally, we present a financial model of fiscal sponsorship by a non-profit organization, implemented in 2022, to ensure the long-term success and sustainability of Arctos. We attribute Arctos longevity of nearly three decades to its core development principles of standardization, flexibility, interdisciplinarity, and connectivity within a nimble development model for addressing novel needs and information types in response to changing technology, workflows, ethical considerations, and regulations.

bioinformatics↗

bioRxiv2023

Regulation of adipocyte dedifferentiation at the skin wound edge

Adipocytes have diverse roles in energy storage and metabolism, inflammation, and tissue repair. Mature adipocytes have been assumed to be terminally differentiated cells. However, recent evidence suggests that adipocytes retain substantial phenotypic plasticity, with potential to dedifferentiate into fibroblast-like cells under physiological and pathological conditions. Here, we develop a two-step lineage tracing approach based on the observation that fibroblasts express platelet-derived growth factor receptor alpha (Pdgfra) while adipocytes express Adiponectin (Adipoq) but not Pdgfra. Our approach specifically traces Pdgfra+ cells that originate from Adipoq+ adipocytes. We find many traced adipocytes and fibroblast-like cells surrounding skin wounds, but only a few traced cells localize to the wound center. In agreement with adipocyte plasticity, traced adipocytes incorporate EdU, downregulate Plin1 and PPAR{gamma}, and upregulate SMA. We also investigate the role of potential dedifferentiation signals using constitutively active PDGFR mutation, Pdgfra knockout, or Tgfbr2 knockout models. We find that PDGF and TGF{beta} signaling both promote dedifferentiation, and PDGFR does so independently of TGF{beta}R2. These results demonstrate an intersectional genetic approach to trace the hybrid cell phenotype of Pdgfra+ adipocytes, which may be important for wound repair, regeneration and fibrosis.

developmental biology↗

bioRxiv2023

Extralimital Terrestrials: A reassessment of range limits in Alaska's land mammals

Understanding and mitigating the effects of anthropogenic climate change and development on species requires the ability to track distributional changes over time. This is particularly true for species occupying high-latitude regions, which are experiencing a greater magnitude of climate change than the rest of the world. In North America, ranges of many mammals reach their northernmost extent in Alaska, positioning this region at the leading edge of climate-induced distribution change. Over a decade has elapsed since the publication of the last spatial assessments of terrestrial mammals in the state. We compared public occurrence records against commonly referenced range maps to evaluate potential extralimital records and develop repeatable baseline range maps. We compared occurrence records from the Global Biodiversity Information Facility for 64 terrestrial mammals native to mainland Alaska against a variety of range estimates (International Union for the Conservation of Nature, Alaska Gap Analysis Project, and the published literature). We mapped extralimital records and calculated proportions of occurrences encompassed by range extents. We also evaluated extralimital records against published species models, highlighted extralimital observations on U.S. Department of Interior lands, and report on two species of bats new to Alaska since 2014. Range comparisons identified 6,848 extralimital records belonging to 39 of 112 (34.8%) Alaskan species. On average, the Alaska Gap Analysis Project encompassed 95.5% of occurrence records and ranges were deemed accurate (> 90.0% correct) for 31 of 37 species, but overestimated extents for 13 species. International Union for Conservation of Nature range maps encompassed 68.1% of occurrence records and were > 90% accurate for 17 of 39 species. Results are either the product of improved sampling and digitization or represent actual geographic range expansions. Here we provide new data-driven range maps, update standards for the archival of museum-quality locational records and offer recommendations for mapping range changes for monitoring and conservation.

ecology↗

bioRxiv2021

An activating mutation in Pdgfrb causes skeletal stem cell defects with osteopenia andovergrowth in mice

Autosomal dominant PDGFR{beta} gain-of-function mutations in mice and humans cause a spectrum of wasting and overgrowth disorders afflicting the skeleton and other connective tissues, but the cellular origin of these disorders remains unknown. We demonstrate that skeletal stem cells (SSCs) isolated from mice with a gain-of-function D849V point mutation in PDGFR{beta} exhibit SSC colony formation defects that parallel the wasting or overgrowth phenotypes of the mice. Single-cell RNA transcriptomics with the SSC colonies demonstrates alterations in osteoblast and chondrocyte precursors caused by PDGFR{beta}D849V. Mutant SSC colonies undergo poor osteogenesis in vitro and mice with PDGFR{beta}D849V exhibit osteopenia. Increased expression of Sox9 and other chondrogenic markers occurs in SSC colonies from mice with PDGFR{beta}D849V. Increased STAT5 phosphorylation and overexpression of Igf1 and Socs2 in PDGFR{beta}D849V SSCs suggests that overgrowth in mice involves PDGFR{beta}D849V activating the STAT5-IGF1 axis locally in the skeleton. Our study establishes that PDGFR{beta}D849V causes osteopenic skeletal phenotypes that are associated with intrinsic changes in SSCs, promoting chondrogenesis over osteogenesis.

developmental biology↗