The PTK7-Related Transmembrane Proteins Off-track and Off-track 2 Are Co-receptors for <i>Drosophila</i> Wnt2 Required for Male Fertility

<div><p>Wnt proteins regulate many developmental processes and are required for tissue homeostasis in adult animals. The cellular responses to Wnts are manifold and are determined by the respective Wnt ligand and its specific receptor complex in the plasma membrane. Wnt receptor complexes contain a member of the Frizzled family of serpentine receptors and a co-receptor, which commonly is a single-pass transmembrane protein. Vertebrate protein tyrosine kinase 7 (PTK7) was identified as a Wnt co-receptor required for control of planar cell polarity (PCP) in frogs and mice. We found that flies homozygous for a complete knock-out of the <i>Drosophila</i> PTK7 homolog <i>off track</i> (<i>otk</i>) are viable and fertile and do not show PCP phenotypes. We discovered an <i>otk</i> paralog (<i>otk2</i>, <i>CG8964</i>), which is co-expressed with <i>otk</i> throughout embryonic and larval development. Otk and Otk2 bind to each other and form complexes with Frizzled, Frizzled2 and Wnt2, pointing to a function as Wnt co-receptors. Flies lacking both <i>otk</i> and <i>otk2</i> are viable but male sterile due to defective morphogenesis of the ejaculatory duct. Overexpression of Otk causes female sterility due to malformation of the oviduct, indicating that Otk and Otk2 are specifically involved in the sexually dimorphic development of the genital tract.</p>