Biology subjects

Oxvig, C.

Publications and source records attributed to Oxvig, C..

8 recordsLinked to original sources

bioRxiv2026

SorCS2 controls Wnt signaling homeostasis during neurodevelopment by regulating Ror2 activity and trafficking

Wnt signaling orchestrates key developmental processes, yet mechanisms restricting its spatial and temporal activity remain incompletely understood. Here we identify SorCS2, a VPS10p-domain sorting receptor, as a conserved regulator of Wnt signaling homeostasis. Integrating proteomics, cell biology, embryology, and vertebrate models, we show that SorCS2 interacts with the noncanonical Wnt receptor Ror2 and controls its trafficking, Wnt5a-induced internalization, and lysosomal degradation. In mouse dopaminergic progenitors, SorCS2 deficiency enhances responsiveness to canonical and noncanonical Wnt ligands, increases Ror2 phosphorylation, and amplifies downstream signaling of both Wnt signaling cascades. Loss of SorCS2 further disrupts the ligand-receptor feedback loop, leading to elevated Ror2, Wnt5a, and Wnt1 expression, accelerated proliferation and neurogenesis, and increased expression of Tcf4, a gene implicated in neuropsychiatric disorders. Across vertebrate systems, SorCS2-dependent control of Ror2 signaling is required for anterior-posterior axis elongation, convergent extension, somitogenesis, and brain morphogenesis. These findings define a SorCS2-dependent sorting mechanism that fine-tunes morphogen receptor signaling during vertebrate neurodevelopment.

developmental biology↗

bioRxiv2026

Metabolic vulnerability is a target of the antineoplastic effect of breastfeeding.

Lactation is associated with a protective effect against breast and ovarian cancer as well as against cardiovascular diseases suggesting a systemic effect. Here, we show that the serum of lactating mice and breastfeeding mothers have targeted antineoplastic effects, while serum from virgin mice and matched post-partum but non-lactating women do not. The effect is specific to cancer cells expressing Pappalysin-A (PAPP-A), a target that is shared among diseases affected by breastfeeding. RNAseq revealed that lactating serum inhibits mitochondrial function and we found that PAPP-A alone lowers mitochondrial function, suggesting that lactation serum acts by exploiting the metabolic vulnerability of these cancer cells. Using serum proteomics, we identified corticotropin release factor (CRF) as being unique to serum of lactating women and we show that CRF alone mimics the mitochondrial and anti-tumorigenic effect of lactating serum. Blocking the CRF receptor, inhibits the protective effect of lactating serum. Since CRF has shown efficacy in the clinic in other settings, our findings raise the possibility to extend its use to mimic or enhance the protective effect of breastfeeding. SummaryWe show that the serum from lactating women has anti-cancer activity and used multi-omics approaches to identify corticotropin release factor as a peptide able to mimic the effect of lactating serum by targeting cells with low mitochondrial activity.

cancer biology↗

bioRxiv2024

HSP60 chaperone deficiency disrupts the mitochondrial matrix proteome and dysregulates cholesterol synthesis

Mitochondrial proteostasis is critical for cellular function and survival. HSP60 is a molecular chaperone that interacts with more than 260 mitochondrial matrix proteins to assist in their folding and few genetic variants of HSP60 are compatible with life. The few reported human patients with HSP60 variants show phenotypes of neurodevelopmental delay associated with brain hypomyelination. It is currently unknown how deficiency of the HSP60 links to hypomyelination. Here, we studied the onset and progression of HSP60 deficiency in: (1) a HSP60 mutation-inducible cell system, (2) skin fibroblasts from patients with disease-associated HSP60 variants, and (3) zebrafish HSP60 knockout larvae. Collectively, we show how HSP60 deficiency leads to pervasive dysfunctions: (1) downregulated mitochondrial matrix proteome, (2) transcriptional activation of cytosolic stress responses, (3) and lipid accumulation with dysregulated cholesterol biosynthesis. In zebrafish larvae HSP60 deficiency induced early developmental abnormalities. Our comprehensive data identifies HSP60 as a master regulator of mitochondrial proteostasis and suggests a pivotal effect of HSP60 dysfunction on myelination through dysregulation of cholesterol biosynthesis. HighlightsO_LIHSP60 deficiency disrupts mitochondrial matrix proteins activating stress responses C_LIO_LIDisrupted matrix proteome impairs catabolism causing acetyl-CoA shortage C_LIO_LIHSP60 deficiency dysregulates cytosolic cholesterol synthesis C_LIO_LIHsp60 deficiency causes developmental abnormalities in zebrafish larvae C_LIO_LIDysregulated cholesterol synthesis links HSP60 deficiency to hypomyelination C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=59 SRC="FIGDIR/small/578131v1_ufig1.gif" ALT="Figure 1"> View larger version (11K): org.highwire.dtl.DTLVardef@891066org.highwire.dtl.DTLVardef@93ae5borg.highwire.dtl.DTLVardef@19bded0org.highwire.dtl.DTLVardef@414428_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

Beyond Basic Characterization and Omics: Immunomodulatory Roles of Platelet-Derived Extracellular Vesicles Unveiled by Functional Testing

Renowned for their role in hemostasis and thrombosis, platelets are also increasingly recognized for their contribution in innate immunity, immunothrombosis and inflammatory diseases. Platelets express a wide range of receptors, which allows them to reach a variety of activation endpoints and grants them immunomodulatory functions. Activated platelets release extracellular vesicles (PEVs), whose formation and molecular cargo has been shown to depend on receptor-mediated activation and environmental cues. This study compares the immunomodulatory profiles of PEVs generated via activation of platelets by different receptors, glycoprotein VI, C-type lectin-like receptor 2, and combining all thrombin-collagen receptors. Functional assays in vivo in zebrafish and in vitro in human macrophages respectively highlighted distinct homing and secretory responses triggered by the PEVs. In contrast, omics analyses of protein and miRNA cargo combined with physicochemical particle characterization found only subtle differences between the PEV types, which were insufficient to explain their different functional immunomodulatory profiles. Constitutively released PEVs, formed in the absence of an exogenous activator, displayed a disparate activation profile from the receptor induced PEVs. Our findings underscore that PEVs are tunable through receptor-mediated activation. To truly comprehend their role(s) in mediating platelet functions among immune cells, conducting functional assays is imperative. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/570750v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@75a9dborg.highwire.dtl.DTLVardef@e2787corg.highwire.dtl.DTLVardef@543525org.highwire.dtl.DTLVardef@6d1362_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2023

SorCS2 binds progranulin and regulates motor axon outgrowth

Motor neuron development requires an orchestrated action of trophic factors and guidance cues for axons to reach their targets. Here, we identify SorCS2 as a novel receptor for progranulin (PGRN) that is required for motor axon outgrowth in zebrafish and mice. In both species motor neurons express SorCS2, and PGRN is produced in cells juxta-positioned the projecting axon, but in mice the neurons also co-express PGRN. In zebrafish, sorcs2 knockdown produces stunted and aberrantly branched motor axons, and in Sorcs2-/- mice, forelimb innervation and motor neuron regeneration are substantially perturbed; phenotypes also observed in fish and mice lacking PGRN. SorCS2 binds PGRN and while motor neuron cultures from wildtype mice respond to exogenous PGRN by axon outgrowth, knockout neurons are unresponsive. Remarkably, when co-expressed in the same cells, SorCS2 controls secretion of PGRN. We conclude that SorCS2 navigates motor neuron development and enables axon regeneration through binding of PGRN.

developmental biology↗

bioRxiv2020

Identification of stromal genes differentially expressed in lobular breast cancer highlights role for pregnancy-associated-plasma protein-A

BackgroundInvasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer and exhibits a number of clinico-pathological characteristics that are distinct from the more common invasive ductal carcinoma (IDC). Despite these differences, ILC is treated in the same way as IDC. We set out to identify alterations in the tumor microenvironment (TME) of ILC with potential clinical significance. MethodsWe used laser-capture microdissection (LCM) to separate tumor epithelium from stroma in 23 ER+ ILC samples. Gene expression analysis was used to identify genes that are enriched in the stroma of ILC, but not IDC or normal breast. Results45 genes involved in regulation of the extracellular matrix (ECM) were enriched in the stroma of ILC, but not stroma from ER+ IDC or normal breast. Of these, 10 were expressed in cancer-associated fibroblasts (CAFs) and were increased in ILC compared to IDC in bulk gene expression datasets. PAPPA was the most enriched in the stroma compared to the tumor epithelial compartment in ILC. PAPPA encodes pregnancy-associated plasma protein-A (PAPP-A), a metalloproteinase that cleaves insulin-like binding protein-4 (IGFBP-4) increasing IGF-1 bioavailability and subsequent downstream signaling. Analysis of PAPPA and IGF1 associated genes identified a paracrine signaling pathway and active PAPP-A was shown to be secreted from primary CAFs. Comprehensive survival analysis across 3000 breast cancers identified PAPPA as a potential ILC-specific prognostic marker. ConclusionsThis is the first study to demonstrate molecular differences in the TME between ILC and IDC and identifies PAPP-A, a CAF-derived proteinase, as a potential prognostic marker.

cancer biology↗

bioRxiv2020

Tracing the in vivo fate of nanoparticles with a "non-self" biological identity

ABSTRACTNanoparticles can acquire a biomolecular corona with a species-specific biological identity. However, “non-self” incompatibility of recipient biological systems is often not considered, for example, when rodents are used as a model organism for preclinical studies of biomolecule-inspired nanomedicines. Using zebrafish embryos as an emerging model for nano-bioimaging, here we unraveled the in vivo fate of intravenously injected 70 nm SiO2 nanoparticles with a protein corona pre-formed from fetal bovine serum (FBS), representing a non-self biological identity. Strikingly rapid sequestration and endolysosomal acidification of nanoparticles with the pre-formed FBS corona were observed in scavenger endothelial cells within minutes after injection. This led to loss of blood vessel integrity and inflammatory activation of macrophages over the course of several hours. As unmodified nanoparticles or the equivalent dose of FBS proteins alone failed to induce the observed pathophysiology, this signifies how the corona enriched with a differential repertoire of proteins can determine the fate of the nanoparticles in vivo. Our findings thus reveal the adverse outcome triggered by incompatible protein coronas and indicate a potential pitfall in the use of mismatched species combinations during nanomedicine development.Competing Interest StatementThe authors have declared no competing interest.View Full Text

pharmacology and toxicology↗

bioRxiv2019

The metalloproteinase Papp-aa functions as a molecular switch linking IGF signaling to adaptive epithelial growth

Human patients carrying inactivating mutations in the pregnancy-associated plasma protein-a2 (PAPP-A2) gene display short status and lower bone mineral density. The underlying mechanisms are not well understood. Using a zebrafish model, here we report a [Ca2+]-dependent mechanism by which Papp-aa regulates bone calcification via promoting Ca2+-transporting epithelial cell (ionocyte) reactivation. Ionocyte, normally quiescent, re-enter the cell cycle in response to low [Ca2+] stress. Deletion of Papp-aa abolished ionocyte reactivation and resulted in a complete lack of calcified bone. Re-expression of Papp-aa, but not its active site mutant, rescued ionocyte reactivation. Inhibition of Papp-aa activity pharmacologically or by overexpressing STC1 or STC2 impaired ionocyte reactivation. Loss of Papp-aa expression or activity resulted in diminished IGF1 receptor-mediated Akt-Tor signaling activity in ionocytes and expression of a constitutively active Akt rescued ionocyte reactivation. Biochemically, Papp-aa cleaved Igfbp5a, a high-affinity IGF binding protein specifically expressed in ionocytes. Under normal [Ca2+] conditions, the Papp-aa-mediated Igfbp5a proteolysis was suppressed and IGFs sequestered in the IGF/Igfbp5a complex. Forced release of IGFs from the complex was sufficient to activate the IGF-Akt-Tor signaling and promote ionocyte reactivation. These findings suggest that Papp-aa functions as a [Ca2+]-regulated molecular switch linking IGF signaling to adaptive epithelial growth and bone calcification.

developmental biology↗