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马赛克热点PIK3CA突变导致非细胞自主血管过度生长和在疾病发病时泛血统失调

Hannah Brunsdon, Nuoya Wang, Micha Sam Brickman Raredon

bioRxiv : the preprint server for biology

|January 23, 2026

概括

马赛克PIK3CA突变通过非自主影响细胞导致过度生长. 斑马鱼模型揭示了突变细胞之外的普遍发育效应,这表明与PIK3CA相关的过度生长谱 (PROS) 的新治疗点.

科学领域:

遗传学和发育生物学
分子生物学分子生物学
斑马鱼建模斑马鱼建模

背景情况:

马赛克功能增长的PIK3CA突变导致与PIK3CA相关的过度生长谱 (PROS),导致组织过度生长的严重程度不同.
目前的理解将疾病的严重程度归因于基因型,细胞类型和突变时间,但并不能完全解释受影响组织的过度生长模式或低突变负担.
有证据表明,PROS突变诱导过度生长非细胞自主,但潜在的机制仍然不清楚.

研究的目的:

使用马赛克斑马鱼模型研究与PIK3CA相关的过度生长的非细胞自主机制.
想象和分析突变PIK3CA细胞对活动物早期胚胎发育的影响.
了解PIK3CA突变在直接受影响的细胞和血统之外的更广泛的发育影响.

主要方法:

开发具有热点PIK3CA突变 (pik3ca^PROS) 过度表达的马赛克斑马鱼模型.
在活斑马鱼中观察胚胎血管缺陷 (VMs) 和幼虫过度生长.
在VM出现之前,对pik3ca^PROS马赛克斑马鱼的单细胞转录组学分析.

主要成果:

斑马鱼模型回顾了PROS特征,包括血管系统形和组织过度生长.
血管系统形很少表达PROS;突变细胞经常与形相邻.
单细胞转录组学揭示了大多数pik3ca^PROS细胞是不成熟的或少数的,但导致了全球细胞命运变化,广泛的基因表达异常和改变细胞通信.

结论:

PIK3CA突变可以通过非细胞自主信号诱导过度生长,影响多个细胞系.
除了PI3K激活外,针对传播过度生长的间接信号通路可能为PROS提供治疗效益.
斑马鱼模型为PIK3CA突变的普遍发育影响提供了关键的见解,超越了突变细胞本身.

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