Experiments in mouse embryonic stem cells, which reside in the naive state (reviewed in Smith, 2017), have indicated a role for WNT/β-catenin signaling in self renewal and maintenance of pluripotency ( Hao et al., 2006 Ogawa et al., 2006 Sato et al., 2004 ten Berge et al., 2011). The role of WNT signaling in the regulation of pluripotency is dependent on both the developmental stage of the cells and on the level of signaling. Human pluripotent stem (hPS) cells provide a powerful in vitro system to study early processes of human development. Because of the lack of selectivity between WNTs and their receptors in vitro and the paucity of purified and biologically active WNT proteins, it has not been possible to address whether engagement of a single WNT receptor is sufficient to elicit the complex biological processes affected by WNT. ![]() Such observations have led to the prevailing and oversimplified view that specific WNT-receptor interactions are not as critical as the ensuing downstream signaling event. In experimental settings, activation of WNT signaling with either purified recombinant WNT proteins, such as Wnt3a, or with small molecule agonists, such as GSK3 inhibitors, frequently elicits the desired downstream transcriptional effect. With the human genome encoding 19 WNTs and an equally large number of WNT receptors (Frizzled 1–10, LRP5 and 6, ROR1 and 2, RYK, PTK7 and more reviewed in Niehrs, 2012), relatively little is known about signaling specificities between WNT ligands and their receptors. Deregulated WNT activity is associated with many pathologies, including degenerative and age-related diseases and cancer (reviewed in Nusse and Clevers, 2017). WNTs are highly conserved, lipid-modified secreted proteins with a broad range of activities throughout development and during adult tissue homeostasis (reviewed in Clevers et al., 2014). This demonstrates that selective engagement and activation of FZD7 signaling is sufficient to promote mesendodermal differentiation of hPS cells. Treatment of human pluripotent stem (hPS) cells with F7L6 initiates transcriptional programs similar to those observed during primitive streak formation and subsequent gastrulation in the mammalian embryo. In contrast to Wnt3a, F7L6 engages only FZD7 and none of the other FZD proteins. F7L6 potently activates WNT/β-catenin signaling in a manner similar to Wnt3a. Here, we describe an engineered protein, called F7L6, comprised of antibody-derived single-chain variable fragments, that selectively binds to human FZD7 and the co-receptor LRP6. ![]() Studying selectivity between WNTs and FZDs has been hampered by the paucity of purified WNT proteins and by their apparent non-selective interactions with the FZD receptors. WNT proteins are secreted symmetry breaking signals that interact with cell surface receptors of the FZD family to regulate a multitude of developmental processes.
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