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

## TL;DR

This study shows how the protein TEAD1a helps control early neutrophil development and could lead to new treatments for neutropenia.

## Contribution

The study reveals TEAD1a's role in transcriptional priming during early neutrophil lineage specification in zebrafish.

## Key findings

- TEAD1a is essential for neutrophil lineage specification before hematopoietic stem cell formation.
- TEAD1a/YAP1 complexes activate Notch1 signaling to trigger Spi1/Cebpα transcriptional cascade in myeloid progenitors.
- Disruption of TEAD1a or YAP1 interaction causes profound neutropenia in zebrafish models.

## 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.

This study discovered that the protein TEAD1a is crucial for neutrophil development. In zebrafish models, disrupting TEAD1a or its interaction with partner protein YAP1 caused severe neutrophil deficiency. TEAD1a functions during the early HSC stage, activates Notch1 signaling in the GMP stage, and triggers Spi1 and Cebpα to drive neutrophil terminal differentiation and production. This identifies TEAD1a as a potential new target for treating neutropenia.