Advances in the Evolution and Function of the RSPO Gene Family

The RSPO gene family, comprising RSPO1, RSPO2, RSPO3, and RSPO4, encodes cysteine-rich secreted glycoproteins. These proteins serve as key activators of the Wnt signaling pathway, a fundamental cascade critical for orchestrating developmental processes—such as embryogenesis and organ formation—and regulating essential cellular activities, including stem cell maintenance, proliferation, and differentiation. First identified in model organisms like mice and zebrafish, studies of the RSPO family have yielded foundational insights into developmental signaling. Yet, their evolutionary trajectory remains elusive, obscured by complex patterns of gene duplication, loss, and adaptation across divergent lineages, coupled with a scarcity of fossil and genomic data. Current research leverages comparative genomics, sophisticated phylogenetic reconstructions, and functional assays to unravel their enigmatic origin, trace their diversification, and pinpoint their specific roles across the tree of life. This review synthesizes recent advances in deciphering RSPO-mediated signaling, aiming to establish a robust framework for future investigations. Such work will encompass functional validation in non-model organisms and the intricate dissection of molecular mechanisms, ultimately striving to propel precision medicine targeting Wnt-related disorders.