Spliceosomal component Sf3b1 is essential for hematopoietic differentiation in zebrafish.
SF3B1 (Splicing factor 3b, subunit 1) is one of the most commonly mutated factors in myelodysplastic syndrome (MDS). Although the genetic correlation between SF3B1 mutations and MDS etiology are quite strong, no in vivo model currently exists to explore how SF3B1 loss alters blood cell development. Using zebrafish mutants, we show here that proper function of Sf3b1 is required for all hematopoietic lineages. As in MDS patients, zebrafish sf3b1 mutants develop a macrocytic-anemia-like phenotype due to a block in maturation at a late progenitor stage. The mutant embryos also develop neutropenia, because their primitive myeloid cells fail to mature and turn on differentiation markers such as l-plastin and myeloperoxidase. In contrast, production of definitive hematopoietic stem and progenitor cells (HSPCs) from hemogenic endothelial cells within the dorsal aorta is greatly diminished, whereas arterial endothelial cells are correctly fated. Notch signaling, imperative for the endothelial-to-hematopoietic transition, is also normal, indicating that HSPC induction is blocked in sf3b1 mutants downstream or independent of Notch signaling. The data demonstrate that Sf3b1 function is necessary during key differentiation fate decisions in multiple blood cell types. Zebrafish sf3b1 mutants offer a novel animal model with which to explore the role of splicing in hematopoietic development and provide an excellent in vivo system with which to delve into the question of why and how Sf3b1 dysfunction is detrimental to hematopoietic differentiation, which could improve MDS diagnosis and treatment.
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA; Gottesman Institute for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
Adriana
A
De La Garza
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA; Gottesman Institute for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
Rosannah C
RC
Cameron
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA; Gottesman Institute for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
Sara
S
Nik
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA; Gottesman Institute for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
Sara G
SG
Payne
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA; Gottesman Institute for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; Department of Medicine (Oncology), Albert Einstein College of Medicine, Bronx, NY, USA. Electronic address: teresa.bowman@einstein.yu.edu.
Teresa V
TV
Bowman
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015415:Biomarkers; D002454:Cell Differentiation / Q000235:genetics*; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D009154:Mutation; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism; D000072260:RNA Splicing Factors / Q000235:genetics*; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D015027:Zebrafish / Q000235:genetics* / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics*
D015415:Biomarkers; D000072260:RNA Splicing Factors; D051880:Receptors, Notch; C575140:Sf3b1 protein, zebrafish; D029961:Zebrafish Proteins