title: Carboxypeptidase Z (CPZ) modulates Wnt signaling and regulates the development of skeletal elements in the chicken.
abstract: Carboxypeptidase Z (CPZ) is a secreted Zn-dependent enzyme whose biological function is largely unknown. CPZ has a bipartite structure consisting of an N-terminal cysteine-rich domain (CRD) and a C-terminal catalytic domain. In the early chicken embryo CPZ is initially expressed throughout the somites and subsequently becomes restricted to the sclerotome. To initiate a functional analysis of CPZ, a CPZ producing retroviral vector was applied to the presomitic mesoderm at the level of the future wing. This resulted in a loss of the scapular blade and of rostral ribs. Such dysmorphogenesis is preceded by ectopic Pax3 expression in the hypaxial part of the dermomyotome, a region from which the blade of the scapula normally derives. A mutant CPZ, lacking a critical active site glutamate, fails to induce Pax3 expression and does not cause skeletal defects. The induction of Pax3, a Wnt-responsive gene in somites, and the presence of a CRD prompted us to examine whether CPZ affects Wnt signaling. In an in vitro assay we found that CPZ, but not its inactive mutant form, enhances the Wnt-dependent induction of the homeobox gene Cdx1. In addition, immunoprecipitation experiments suggest that the CRD of CPZ acts as a binding domain for Wnt. Taken together these data provide the first evidence for CPZ playing a role in Wnt signaling.
authors.affiliation: Max Planck Institute of Experimental Endocrinology, Hannover, Germany 30625.
authors.forename: Carsten
authors.initials: C
authors.lastname: Moeller
authors.forename: Eric C
authors.initials: EC
authors.lastname: Swindell
authors.forename: Andreas
authors.initials: A
authors.lastname: Kispert
authors.forename: Gregor
authors.initials: G
authors.lastname: Eichele
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002268:Carboxypeptidases / Q000235:genetics / Q000378:metabolism*; D002642:Chick Embryo; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D008969:Molecular Sequence Data; D009024:Morphogenesis / Q000502:physiology; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D012272:Ribs / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism; D012540:Scapula / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology*; D019170:Somites / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins; D060528:Wnt4 Protein
chemical_list: C491273:CDX1 protein, human; C491272:Cdx1 protein, mouse; C491271:Cdx1 protein, rat; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C555581:WNT4 protein, human; D051153:Wnt Proteins; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse; C555583:Wnt4 protein, rat; C068686:Pax3 protein, mouse; C499284:CPZ protein, human; D002268:Carboxypeptidases; C499286:Cpz protein, rat; C022633:serine carboxypeptidase; C499287:carboxypeptidase Z