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Plxnc1 promotes the development of hematopoietic stem and progenitor cells by regulating Rac1-dependent Wnt signaling and DHA Synthesis

ABSTRACT: Hematopoietic stem and progenitor cells (HSPCs) sustain lifelong blood production and originates from hemogenic endothelial cells (HECs) through endothelial-to-hematopoietic transition (EHT) during vertebrate embryogenesis. Although many intrinsic regulators of EHT have been identified, how niche-derived cues are integrated with intracellular signaling and metabolic programs to control HSPCs emergence remains incompletely understood. Here, we identify Plxnc1, a Plexin family receptor specifically enriched in HECs, is essential for HECs specification and definitive HSPCs production in zebrafish. Loss of Plxnc1 impairs definitive hematopoiesis without affecting primitive hematopoiesis or vascular development. Mechanistically, endothelial-derived Sema7a activates Plxnc1 in HECs, leading to Rac1 activation and sustained canonical Wnt/β-catenin signaling. This signaling cascade directly induces transcription of elovl2, which encodes a rate-limiting enzyme for docosahexaenoic acid (DHA) biosynthesis Consequently, Plxnc1 deficiency leads to reduced DHA levels, and exogenous DHA supplementation or elovl2 overexpression effectively rescue the hematopoietic defects. Taken together, these findings establish a Sema7a-Plxnc1-Rac1-Wnt/β-catenin-Elovl2-DHA axis that couples endothelial niche signaling to lipid metabolic control during definitive hematopoiesis

ORGANISM(S): Danio rerio

PROVIDER: GSE336389 | GEO | 2026/08/18

REPOSITORIES: GEO

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