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

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.