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Custos Controls Β-Catenin to Regulate Head Development During Vertebrate Embryogenesis

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Custos Controls Β-Catenin to Regulate Head Development During Vertebrate Embryogenesis Custos controls β-catenin to regulate head development during vertebrate embryogenesis Yuko Komiyaa,1, Noopur Mandrekara, Akira Satob, Igor B. Dawidc,2, and Raymond Habasa,2 aDepartment of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122; bDepartment of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan; and cSection on Developmental Biology, National Institute of Child Health and Human Development, Bethesda, MD 20892-2790 Contributed by Igor B. Dawid, August 1, 2014 (sent for review June 27, 2014) Precise control of the canonical Wnt pathway is crucial in embryo- and the proteasome (7). In the presence of Wnt signaling, Dvl genesis and all stages of life, and dysregulation of this pathway is blocks this phosphorylation of β-catenin, and the inhibition of implicated in many human diseases including cancers and birth degradation of β-catenin allows for its cytoplasmic accumulation defect disorders. A key aspect of canonical Wnt signaling is the and subsequent nuclear translocation. In the nucleus, β-catenin cytoplasmic to nuclear translocation of β-catenin, a process that complexes with the Lef/Tcf family of transcription factors and remains incompletely understood. Here we report the identification regulates transcription of Wnt-target genes (1). β-catenin binding of a previously undescribed component of the canonical Wnt signal- proteins are known, and they regulate its ability to interact with ing pathway termed Custos, originally isolated as a Dishevelled– Tcf or influence its transcriptional activity (8). The cytoplasmic– interacting protein. Custos contains casein kinase phosphorylation nuclear translocation of β-catenin remains poorly understood, sites and nuclear localization sequences. In Xenopus, custos mRNA as β-catenin has no identified nuclear localization sequences is expressed maternally and then widely throughout embryogenesis. (9–11). It has been proposed that β-catenin may “piggy-back” into Depletion or overexpression of Custos produced defective anterior the nucleus by interacting with factors that traffic this protein head structures by inhibiting the formation of the Spemann-Man- across the nuclear envelope (11, 12). Specifically, β-catenin was gold organizer. In addition, Custos expression blocked secondary proposed to interact with importin-β for nuclear import (13), but axis induction by positive signaling components of the canonical it remains unclear if β-catenin docks with any proteins at the Wnt pathway and inhibited β-catenin/TCF-dependent transcription. nuclear pore for its entry and how this entry is regulated (11). Custos binds to β-catenin in a Wnt responsive manner without af- For nuclear export of β-catenin there is evidence that β-catenin fecting its stability, but rather modulates the cytoplasmic to nuclear may exit via binding to proteins such as Axin (12) and APC (10) translocation of β-catenin. This effect on nuclear import appears to using a Ran and CRM1-independent mechanism (11). Alterna- be the mechanism by which Custos inhibits canonical Wnt signaling. tively, β-catenin can interact with RanBP3 to be exported from The function of Custos is conserved as loss-of-function and gain- the nucleus (14). In the present work we show that Custos of-function studies in zebrafish also demonstrate a role for Custos inhibits canonical Wnt signaling in frog embryos and cultured in anterior head development. Our studies suggest a role for Custos cells by antagonizing nuclear import of β−catenin. in fine-tuning canonical Wnt signal transduction during embryo- genesis, adding an additional layer of regulatory control in the Wnt- Results β-catenin signal transduction cascade. In our efforts to understand how Dvl branches the extracellular Wnt signal into different intracellular signaling cascades, we nderstanding the molecular mechanisms of pattern forma- Ution during embryogenesis remains a challenge for biolo- Significance gists. One key family of signaling molecules that have been shown to play crucial roles in this process is the Wnt family. Wnt Canonical Wnt pathway is essential for primary axis formation proteins are conserved secreted glycoproteins that govern major and establishment of basic body pattern during embryogenesis. developmental processes including cell fate determination, cell Defects in Wnt signaling have also been implicated in tumori- proliferation, cell motility and establishment of the primary axis genesis and birth defect disorders. Here we characterize a novel and head formation during vertebrate development (1, 2). In component of canonical Wnt signaling termed Custos and show addition to regulating embryonic development, defects in Wnt that this protein binds to and modulates β-catenin nuclear signaling have also been implicated in tumorigenesis and birth translocation in the canonical Wnt signal transduction cascade. defect disorders (1). The Wnt ligands bind to their cognate Our functional characterization of Custos further shows that this receptors and coreceptors, which are encoded in the Frizzled protein has a conserved role in development, being essential for (Fz) and Lipoprotein Related Protein 5/6 (LRP5/6) gene fami- organizer formation and subsequent anterior development in lies (2, 3). Through intensive studies, a molecular signaling the Xenopus and zebrafish embryo. These studies unravel a new pathway has emerged. Upon the binding of Wnt to a receptor layer of regulation of canonical Wnt signaling that might pro- complex, a signal is transduced to the cytoplasmic phosphopro- vide insights into mechanisms by which deregulated Wnt sig- tein Dishevelled (Dvl); at the level of Dvl and using distinct naling results in pathological disorders. domains within Dvl, the Wnt signal branches into two signaling pathways, a “canonical” and a “noncanonical” pathway (3). A Author contributions: I.B.D. and R.H. designed research; Y.K., N.M., and A.S. performed large number of Dvl-interacting proteins have been identified research; Y.K., I.B.D., and R.H. wrote the paper; and R.H. directed the project. that function to link Dvl to the downstream pathway or influence The authors declare no conflict of interest. its ability to signal, including Casein Kinase 1 (CK1) (4) for the Data deposition: The sequence reported in this paper has been deposited in the GenBank database (accession no. KM235953). canonical signaling and Daam1 (5) for the noncanonical Wnt 1Present address: Department of Pharmacology, Rutgers Robert Wood Johnson Medical signaling pathway (3). For canonical signaling, which acts in axis School, Piscataway, NJ 08854. formation, Wnt signaling through Dvl induces the stabilization of 2 β β To whom correspondence may be addressed. Email: [email protected] or idawid@mail. cytosolic -catenin (6). In the absence of Wnt signaling, -catenin nih.gov. BIOLOGY β is phosphorylated by CK1 and GSK3 , and targeted by a de- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. DEVELOPMENTAL struction complex for ubiquitination and degradation by β-TrCP 1073/pnas.1414437111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1414437111 PNAS | September 9, 2014 | vol. 111 | no. 36 | 13099–13104 Downloaded by guest on October 2, 2021 screened for binding partners of Dvl using a PDZ containing Dvl and S3 A and B). The expression of Dvl with Custos resulted in fragment as bait in a yeast two-hybrid assay under conditions a downshift in the migration of Custos on SDS/PAGE gels due previously described (5). This screen uncovered a previously to a dephosphorylation of this protein (Fig. S3C), and we found uncharacterized protein that we have named Custos, for the that Custos interacted with CK1 and was a substrate for CK1 Latin term for “guard” or “keeper.” Here we report on the bi- (Fig. S2 F and G). These results suggest Custos is a potential ological function of Custos during Xenopus and zebrafish em- novel regulator of Wnt signaling pathway. bryogenesis. Xenopus Custos (KM235953) encodes a 237-aa To uncover Custos’ potential role during embryogenesis, we first protein that contains two putative CK1 phosphorylation sites as examined the temporal and spatial expression pattern of custos well as two clusters of dual putative nuclear localization signals RNA in the Xenopus embryo. RT-PCR analysis revealed stable (NLS) (Fig. 1A). Xenopus Custos shares 45%, 46%, 48%, and 50% expression of custos maternally to the tadpole stage (Fig. S4A). In amino acid sequence identity to zebrafish (NP_001008602), rat situ hybridization demonstrated broad expression of custos from (NP_001009630), mouse (NP_082487), and human (NP_075046) egg to cleavage-stage embryos (Fig. S4B). During the neurula Custos, respectively, indicating that Custos is conserved among stage, custos was highly expressed in the neural plate and neural custos vertebrates; however, no ortholog based on sequence comparison fold. Strong expression of was also detected in brain, eyes, was identified in invertebrates (Fig. S1). and spinal cord at the tadpole stage. Xenopus We observed that Custos binds to Dvl in coimmunoprecipi- To delineate the biological function of Custos during tation studies and this interaction was negatively regulated by embryogenesis, we conducted gain-of-function (RNA expression) Wnt stimulation (Fig. S2 A and B). The interacting domains were and loss-of-function studies (antisense Morpholino oligonucleotide, D mapped to between the PDZ and DEP domains of Dvl, and
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