Ccd1, a novel protein with a DIX domain, is a positive regulator in the Wnt signaling during zebrafish neural patterning.
Wnt signaling plays a crucial role in directing cell differentiation, polarity, and growth. In the canonical pathway, Wnt receptors activate Dishevelled (Dvl), which then blocks the degradation of a key signal transducer, beta-catenin, leading to the nuclear accumulation of beta-catenin and induction of Wnt target genes through TCF/LEF family transcription factors. Here we identified a novel zebrafish gene encoding Ccd1, which possesses a DIX (Dishevelled-Axin) domain. DIX domains are essential for the signal transduction of two major Wnt downstream mediators, Dvl and Axin. Ccd1 formed homomeric and heteromeric complexes with Dvl and Axin and activated TCF-dependent transcription in vitro. In addition, overexpression of ccd1 in zebrafish embryos led to a reduction in the size of the eyes and forebrain (posteriorization), as seen with wnt8 overexpression, whereas a dominant-negative ccd1 (DN-ccd1) caused the opposite phenotype. Furthermore, the Wnt activation phenotype induced by ccd1 was inhibited by the expression of axin1 or DN-ccd1, and the wnt8 overexpression phenotype was rescued by DN-ccd1, suggesting that Ccd1 functions downstream of the Wnt receptor and upstream of Axin. These results indicate that Ccd1 is a novel positive regulator in this Wnt signaling pathway during zebrafish neural patterning.
Shiomi
Kensuke
K
Department of Molecular Neurobiology, Institute of Basic Medical Sciences, University of Tsukuba, 1-1-1 Tennoudai, 305-8575, Tsukuba, Ibaraki, Japan.
Uchida
Hiroshi
H
Keino-Masu
Kazuko
K
Masu
Masayuki
M
D000595:Amino Acid Sequence; D000818:Animals; D060466:Axin Protein; D001665:Binding Sites; D019521:Body Patterning / Q000502:physiology*; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism; D004625:Embryo, Nonmammalian; D005124:Eye Abnormalities / Q000235:genetics; D005136:Eye Proteins; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics; D051821:Lymphoid Enhancer-Binding Factor 1; D008969:Molecular Sequence Data; D009420:Nervous System / Q000196:embryology* / Q000378:metabolism; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D051153:Wnt Proteins; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism*
C555451:AXIN1 protein, human; D060466:Axin Protein; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D005136:Eye Proteins; D018398:Homeodomain Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; C477319:dixdc1a protein, zebrafish; C094521:wnt8a protein, zebrafish; C094670:MARK2 protein, human; D017346:Protein Serine-Threonine Kinases