Secreted frizzled-related protein 1a regulates hematopoietic development in a dose-dependent manner

Hematopoietic stem and progenitor cells (HSPCs) are only generated during embryonic development, and their identity specification, emergence from the floor of the dorsal aorta, and proliferation are all tightly regulated by molecular mechanisms such as signaling cues. Among these, Wnt signaling is crucial for HSPC specification, differentiation, and self-renewal, requiring precise regulation for proper development and homeostasis. Wnt signaling begins when a Wnt ligand binds to cell surface receptors, such as those encoded by the frizzled gene family, activating intracellular pathways that regulate gene expression. Secreted frizzled-related proteins (Sfrps) are known to modulate Wnt signaling, acting as both agonists and antagonists. However, the in vivo roles of Sfrps in HSPC development are not fully understood. Here, we show that Sfrp1a influences zebrafish HSPC development and hematopoietic differentiation in a dose-dependent manner. Sfrp1a loss-of-function animals display an upregulation of canonical Wnt signaling, increased HSPC proliferation, and reduced differentiation into lymphoid and myeloid lineages. Conversely, low-dose overexpression of sfrp1a leads to decreased HSPC numbers and enhanced lymphoid differentiation. High-dose sfrp1a overexpression mimics the loss-of-function phenotype, with elevated canonical Wnt signaling, increased HSPCs, and decreased lymphoid and myeloid differentiation. These results emphasize the importance of dose-dependent Sfrp regulation, paralleling observations in hematopoietic cancers where SFRP1 variants can either promote or inhibit tumor development.