{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:38:46Z","timestamp":1768505926127,"version":"3.49.0"},"posted":{"date-parts":[[2023,2,4]]},"group-title":"Cell Biology","reference-count":52,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,2,4]]},"abstract":"<jats:title>ABSTRACT\/SUMMARY<\/jats:title>\n                <jats:p>The platelet-derived growth factor-BB (PDGF-BB) pathway provides critical regulation of cerebrovascular pericytes, orchestrating their investment and retention within the brain microcirculation. Dysregulated PDGF Receptor-beta (PDGFR\u03b2) signaling can lead to pericyte defects that compromise blood-brain barrier (BBB) integrity and cerebral perfusion, impairing neuronal activity and viability, which fuels cognitive and memory deficits. Receptor tyrosine kinases (RTKs) like PDGF-BB and vascular endothelial growth factor-A (VEGF-A) are often modulated by soluble isoforms of cognate receptors that establish signaling activity within a physiological range. Soluble PDGFR\u03b2 (sPDGFR\u03b2) isoforms have been reported to form by enzymatic cleavage from cerebrovascular mural cells, and pericytes in particular, largely under pathological conditions. However, pre-mRNA alternative splicing has not been widely explored as a possible mechanism for generating sPDGFR\u03b2 variants, and specifically during tissue homeostasis. Here, we found sPDGFR\u03b2 protein in the murine brain and other tissues under normal, physiological conditions. Utilizing brain samples for follow-on analysis, we identified mRNA sequences corresponding to sPDGFR\u03b2 isoforms, which facilitated construction of predicted protein structures and related amino acid sequences. Human cell lines yielded comparable sequences and protein model predictions. Retention of ligand binding capacity was confirmed for sPDGFR\u03b2 by co-immunoprecipitation. Visualizing fluorescently labeled sPDGFR\u03b2 transcripts revealed a spatial distribution corresponding to murine brain pericytes alongside cerebrovascular endothelium. Soluble PDGFR\u03b2 protein was detected throughout the brain parenchyma in distinct regions such as along the lateral ventricles, with signals also found more broadly adjacent to cerebral microvessels consistent with pericyte labeling. To better understand how sPDGFR\u03b2 variants might be regulated, we found elevated transcript and protein levels in the murine brain with age, and acute hypoxia increased sPDGFR\u03b2 variant transcripts in a cell-based model of intact vessels. Our findings indicate that soluble isoforms of PDGFR\u03b2 likely arise from pre-mRNA alternative splicing, in addition to enzymatic cleavage mechanisms, and these variants exist under normal physiological conditions. Follow-on studies will be needed to establish potential roles for sPDGFR\u03b2 in regulating PDGF-BB signaling to maintain pericyte quiescence, BBB integrity, and cerebral perfusion \u2013 critical processes underlying neuronal health and function, and in turn memory and cognition.<\/jats:p>","DOI":"10.1101\/2023.02.03.527005","type":"posted-content","created":{"date-parts":[[2023,2,4]],"date-time":"2023-02-04T09:50:13Z","timestamp":1675504213000},"source":"Crossref","is-referenced-by-count":1,"title":["A Soluble Platelet-Derived Growth Factor Receptor-\u03b2 Originates via Pre-mRNA Splicing in the Healthy Brain and is Differentially Regulated during Hypoxia and Aging"],"prefix":"10.64898","author":[{"given":"Laura 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