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

Abstract

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 Drosophila PTK7 homolog off track (otk) are viable and fertile and do not show PCP phenotypes. We discovered an otk paralog (otk2, CG8964), which is co-expressed with otk 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 otk and otk2 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.

Ig Superfamily Ligand and Receptor Pairs Expressed in Synaptic Partners in Drosophila

“…Asterisk indicates that the interacting partner of the protein is not known yet. Interacting partners for all other proteins in this table have been identified (Johnson et al, 2006, Linnemannstöns et al, 2014, Özkan et al, 2013 and Winberg et al, 2001). …”

Protein tyrosine kinase 7 is essential for tubular morphogenesis of the Wolffian duct

“…Therefore, the mechanisms by which the Wolffian duct undergoes morphogenesis and the key factors that regulate this event were a focus of this study. In view of the importance of protein PTK7 towards morphogenesis of the cochlea and neural tube (Lu et al, 2004), and considering that PTK7 homologs off-track (Otk) and off-track 2 (Otk2) are required for morphogenesis of the ejaculatory duct and male fertility in Drosophila (Linnemannstons et al, 2014), PTK7 was hypothesized to be one of the major regulators of Wolffian duct morphogenesis. To this end, PTK7 conditional knockout mice were used to uncover the normal morphogenic events as well as understanding how Wolffian duct morphogenesis is regulated.…”

PTK7 Faces the Wnt in Development and Disease

“…Surprisingly, although PTK7 appears to be a core regulator of vertebrate PCP, classical PCP phenotypes have so far not been reported for the Drosophila orthologs of PTK7, off-track ( otk ), and off-track2 ( otk2 ). These two genes, which are the result of a tandem gene duplication, function redundantly in the tubular morphogenesis of the male ejaculatory duct, leading to male sterility in the otk, otk2 double mutant (Linnemannstons et al, 2014). Intriguingly, mesoderm-specific knock-out of PTK7 in the mouse resulted in tubular morphogenesis defects in the Wolffian duct, again leading to male sterility (Xu et al, 2016).…”

“…The kinase homology domain of PTK7 lacks catalytic activity (Miller and Steele, 2000; Kroiher et al, 2001), but serves as an interaction site for intracellular signaling molecules like ß-catenin, Dsh, and Src (Shnitsar and Borchers, 2008; Puppo et al, 2011; Andreeva et al, 2014). PTK7 interacts with distinct Wnt receptors including Fz7, LRP6, and Ror2 (Peradziryi et al, 2011; Bin-Nun et al, 2014; Linnemannstons et al, 2014; Martinez et al, 2015; Podleschny et al, 2015), indicating that PTK7 affects canonical and non-canonical Wnt signaling pathways. This is also reflected by its evolutionarily conserved interaction with different Wnt ligands that are supposed to signal via both canonical and non-canonical pathways (Peradziryi et al, 2011; Linnemannstons et al, 2014; Martinez et al, 2015).…”