Tead1a Initiates Transcriptional Priming Through the TEAD1a/YAP‐Notch1‐Spi1/Cebpα Axis to Promote Neutrophil Fate

Abstract Clinical neutropenia, a blood disorder marked by faulty neutrophil production, resists effective treatment due to developmental bottlenecks in granulopoiesis. While the current therapy, such as granulocyte colony‐stimulating factor (G‐CSF), boosts neutrophil counts, its late‐stage action mobilizes dysfunctional cells, underscoring the need for early‐lineage therapeutic interventions. Leveraging zebrafish models, we found that transcriptional enhanced associate domain 1a (TEAD1a) initiates transcriptional priming to govern neutrophil lineage specification preceding hematopoietic stem cell formation. Genetic ablation of TEAD1a or disruption of its interaction with Yes‐associated protein 1 (YAP1) induces profound neutropenia. Mechanistic interrogation reveals that TEAD1a/YAP1 complexes potentiate Notch1‐mediated signaling to activate a Spi1/Cebpα transcriptional cascade during myeloid progenitor specification. This study uncovers a novel developmental regulatory window for myeloid lineage commitment and demonstrates the evolutionarily conserved role of TEAD1a‐mediated transcriptional priming in orchestrating neutrophil development. The discovery of this ultra‐early regulatory node provides a molecularly defined target for generating developmentally competent neutrophils, offering an innovative therapeutic strategy for refractory neutropenia.