{"id":450,"title":"IGF1R trafficking is modulated by VPS25/ESCRT-II in mice and humans to control skeletal fate commitment","title_zh":"VPS25/ESCRT-II 通过调控 IGF1R 运输影响小鼠与人类骨骼命运决定","url":"https://doi.org/10.21203/rs.3.rs-11504315/v1","doi":"10.21203/rs.3.rs-11504315/v1","pmid":null,"journal":"Research Square","kind":"preprint","lang":"en","published_at":"2026-11-02T00:00:00+00:00","fetched_at":"2026-11-08T03:44:14+00:00","authors":["Selleri L","Aguayo VH","Risolino M","de Anda J","Hashem M","Habeeb S","AlAbdi L"],"primary_topic":"animal-models","topics":[{"slug":"animal-models","score":0.8,"hits":["mouse embryos"]}],"topic_score":0.8,"preference_score":0.0,"preference_labels":[],"llm_score":52.0,"final_score":52.0,"score_dims":{"novelty":78,"rigor":65,"impact":45,"relevance":20,"translation":25},"recommend_reason":"机制新颖，揭示 VPS25/ESCRT-II 经 IGF1R 运输调控颅面骨软骨命运；但主题属骨骼发育与罕见先天综合征，与生殖医学/辅助生殖核心关联弱，且为预印本，故不作为生殖每日必读。","keywords":["VPS25","ESCRT-II","IGF1R","颅神经嵴","骨软骨祖细胞","骨骼命运决定"],"selected":0,"story_id":176,"llm_provider":"deepseek","llm_model":"deepseek-flash","llm_effort":"low","source_key":"europepmc-preprints","source_name":"Europe PMC · 预印本（领域内）","source_tier":1,"mention_count":1,"has_interpretation":false,"journal_key":"research-square","journal_tier":"standard","journal_if":null,"is_mock":false,"summary_zh":"研究在小鼠胚胎、颅神经嵴来源细胞及患者成纤维细胞中发现，ESCRT-II 亚基 VPS25 缺失会损害成骨并促使骨软骨祖细胞向软骨命运偏移；机制上活化 IGF1R 在内体蓄积，药物抑制 IGF1R 可在体内外部分挽救谱系身份，提示 ESCRT-II–IGF 信号调控颅面骨骼命运。","summary":"Abstract Cranial neural crest cell (CNCC)-derived osteochondroprogenitors commit to either bone or cartilage by fine-tuning master transcription factors. However, it remains unclear how extracellular cues regulate this critical cell fate decision. Here, we show that loss of VPS25, an ESCRT-II subunit required for lysosomal degradation of activated membrane receptors, impairs ossification in mouse embryos and CNCC-derived cells. VPS25 loss reduces osteogenesis, while upregulating early and late chondrogenic markers in vitro, even under cell culture osteogenic induction. In Vps25 mutant mice, the shift toward cartilage at the expense of bone precedes early chondrogenesis, indicating skewed osteochondroprogenitor fate. Mechanistically, VPS25 loss causes endosomal accumulation of activated insulin-like growth factor 1 receptor (IGF1R) in mutant murine cells and in fibroblasts from patients with biallelic VPS25 variants associated with a fatal congenital developmental syndrome. Pharmacological IGF1R inhibition rescues lineage identity in mutant craniofacial skeletal tissues in vivo and in mutant cultured cells. These findings reveal a previously unrecognized role for ESCRT-II in controlling skeletal fate through IGF signaling, providing new mechanistic insight into skeletal cell fate determination and pointing to IGF1R modulation as a potential avenue for mitigating human craniofacial abnormalities.","interpretation_basis":null,"fulltext_status":null,"interpretation":null,"fulltext":{"available":false,"status":null,"reason":"尚未抓取全文（未入选、分数未达阈值，或还没跑 fulltext 步骤）","pmcid":null,"license":null,"chars":0,"source":null,"fetched_at":null}}