Scholarlink

<p>Hematopoietic stem and progenitor cells (HSPCs) sustain blood cell production by balancing self-renewal and differentiation. While regulatory networks of transcription factors are well established during development of these cells, intrinsic cytoskeletal elements remain unclear. Here we show that the gamma-tubulin ring complex (γ-TuRC), a key regulator of microtubule nucleation, is essential for HSPC expansion in zebrafish. Forward genetic screening identifies the zebrafish <i>smu1347</i> mutant, which exhibits HSPC exhaustion during definitive hematopoiesis. Positional cloning reveals a nonsense mutation in the <i>tubgcp6</i> gene, encoding a core component of γ-TuRC, as responsible for the <i>smu1347</i> phenotype. Mutation of Tubgcp6 causes mitotic arrest, disorganized spindle formation, and increased p53-dependent apoptosis. Time-lapse imaging and lineage tracing further demonstrate that Tubgcp6-deficient HSPCs preferentially undergo symmetric differentiation rather than self-renewal. Disrupting other γ-TuRC subunits (Tubgcp3, Tubgcp4, Tubgcp5) produces similar hematopoietic defects, underscoring the importance of intact microtubule nucleation for stem cell maintenance. These findings identify γ-TuRC-mediated microtubule organization as a critical regulator of HSPC fate and suggest that Tubgcp6 may represent a potential therapeutic target for bone marrow failure syndromes and stem cell exhaustion disorders.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Mutation of Tubgcp6 induces hematopoietic stem and progenitor cell exhaustion in zebrafish

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月6日

查看全文
  • Yuxian Zhang,
  • Li Li,
  • Kemin Chen,
  • Xiaohui Chen,
  • Wei Liu,
  • Wenqing Zhang,
  • Zhibin Huang

摘要

Hematopoietic stem and progenitor cells (HSPCs) sustain blood cell production by balancing self-renewal and differentiation. While regulatory networks of transcription factors are well established during development of these cells, intrinsic cytoskeletal elements remain unclear. Here we show that the gamma-tubulin ring complex (γ-TuRC), a key regulator of microtubule nucleation, is essential for HSPC expansion in zebrafish. Forward genetic screening identifies the zebrafish smu1347 mutant, which exhibits HSPC exhaustion during definitive hematopoiesis. Positional cloning reveals a nonsense mutation in the tubgcp6 gene, encoding a core component of γ-TuRC, as responsible for the smu1347 phenotype. Mutation of Tubgcp6 causes mitotic arrest, disorganized spindle formation, and increased p53-dependent apoptosis. Time-lapse imaging and lineage tracing further demonstrate that Tubgcp6-deficient HSPCs preferentially undergo symmetric differentiation rather than self-renewal. Disrupting other γ-TuRC subunits (Tubgcp3, Tubgcp4, Tubgcp5) produces similar hematopoietic defects, underscoring the importance of intact microtubule nucleation for stem cell maintenance. These findings identify γ-TuRC-mediated microtubule organization as a critical regulator of HSPC fate and suggest that Tubgcp6 may represent a potential therapeutic target for bone marrow failure syndromes and stem cell exhaustion disorders.