Key result
Angptl5 loss-of-function expands zebrafish myeloid progenitors ~2.7-fold by dampening retinoic acid signaling.
Why the study?
Retinoic acid is a key regulator of hematopoiesis, but the mechanisms that modulate retinoic acid signaling in hematopoietic processes remain poorly understood.
Does Angptl5 regulate primitive hematopoiesis by modulating retinoic acid signaling through an Integrin α6lβ5-ERK-Junb-dhrs9 pathway in zebrafish embryos?
Does Angptl5 regulate primitive hematopoiesis by modulating retinoic acid signaling through an Integrin α6lβ5-ERK-Junb-dhrs9 pathway in zebrafish embryos?
This preclinical study identifies a novel Angptl5-Integrin α6lβ5-ERK-Junb-Dhrs9 signaling cascade that promotes retinoic acid biosynthesis to restrict excessive myeloid and erythroid progenitor expansion during zebrafish primitive hematopoiesis.
Angptl5 loss-of-function expands zebrafish hematopoietic progenitors; hypothesis-generating for retinoic acid signaling and leaves open mammalian or clinical relevance.
Homeostasis is essential for hematopoiesis, and its dysregulation can lead to severe pathological conditions. Retinoic acid (RA) is a key regulator that exerts concentration-dependent effects on both embryonic and adult hematopoiesis. However, the mechanisms that modulate RA signaling in hematopoietic processes remain poorly understood. Using zebrafish as a model, we identified angiopoietin-like protein 5 (Angptl5) as a critical regulator of hematopoietic homeostasis. Loss of Angptl5 function resulted in myeloid hyperplasia in the anterior lateral plate mesoderm (ALPM) and anterior expansion of erythroid progenitors in the posterior lateral plate mesoderm (PLPM)—phenotypes consistent with attenuated RA signaling. Molecular analyses confirmed impaired RA signaling in angptl5 Δ10/Δ10 mutants, and exogenous RA supplementation fully rescued the hematopoietic defects. Mechanistically, we found that Angptl5 transcriptionally activates retinol dehydrogenase dhrs9 through its interaction with Integrin α6lβ5. Our findings establish Angptl5 as a novel and essential regulator of embryonic hematopoiesis and reveal a previously unrecognized mechanism controlling hematopoietic homeostasis. These insights position Angptl5 as a potential therapeutic target for hematological disorders.
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Mo et al. (2026) studied Primitive hematopoiesis. Angptl5 loss-of-function (CRISPR/Cas9 angptl5 Δ10/Δ10 mutation) and rescue via mRNA or retinoic acid vs. Wild-type (WT) AB strain or uninjected/untreated mutant zebrafish embryos was evaluated on Expansion of spi1b+ myeloid progenitors in the anterior lateral plate mesoderm and gata1a+ erythroid progenitors in the posterior lateral plate mesoderm (p=<0.01). Angptl5 loss-of-function in zebrafish embryos significantly increased myeloid (0.442% vs 0.165%, P<0.01) and erythroid (2.652% vs 1.483%) progenitors by attenuating Integrin α6lβ5-ERK-Junb-mediated retinoic acid signaling.
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