title: CXXC5 is a novel BMP4-regulated modulator of Wnt signaling in neural stem cells.
abstract: Bone morphogenetic proteins such as BMP4 are essential for proper development of telencephalic forebrain structures and induce differentiation of telencephalic neural stem cells into a variety of cellular fates, including astrocytic, neuronal, and mesenchymal cells. Little is yet understood regarding the mechanisms that underlie the spatiotemporal differences in progenitor response to BMP4. In a screen designed to identify novel targets of BMP4 signaling in telencephalic neural stem cells, we found the mRNA levels of the previously uncharacterized factor CXXC5 reproducibly up-regulated upon BMP4 stimulation. In vivo, CXXC5 expression overlapped with BMP4 adjacent to Wnt3a expression in the dorsal regions of the telencephalon, including the developing choroid plexus. CXXC5 showed partial homology with Idax, a related protein previously shown to interact with the Wnt-signaling intermediate Dishevelled (Dvl). Indeed CXXC5 and Dvl co-localized in the cytoplasm and interacted in co-immunoprecipitation experiments. Moreover, fluorescence resonance energy transfer (FRET) experiments verified that CXXC5 and Dvl2 were located in close spatial proximity in neural stem cells. Studies of the functional role of CXXC5 revealed that overexpression of CXXC5 or exposure to BMP4 repressed the levels of the canonical Wnt signaling target Axin2, and CXXC5 attenuated Wnt3a-mediated increase in TOPflash reporter activity. Accordingly, RNA interference of CXXC5 attenuated the BMP4-mediated decrease in Axin2 levels and facilitated the response to Wnt3a in neural stem cells. We propose that CXXC5 is acting as a BMP4-induced inhibitor of Wnt signaling in neural stem cells.
authors.affiliation: CoE in Developmental Biology for Regenerative Medicine (CEDB/DBRM), Department of Neuroscience, Karolinska Institutet, SE17177 Stockholm, Sweden.
authors.forename: Therese
authors.initials: T
authors.lastname: Andersson
authors.forename: Erik
authors.initials: E
authors.lastname: Södersten
authors.forename: Joshua K
authors.initials: JK
authors.lastname: Duckworth
authors.forename: Anna
authors.initials: A
authors.lastname: Cascante
authors.forename: Nicolas
authors.initials: N
authors.lastname: Fritz
authors.forename: Paola
authors.initials: P
authors.lastname: Sacchetti
authors.forename: Igor
authors.initials: I
authors.lastname: Cervenka
authors.forename: Vitezslav
authors.initials: V
authors.lastname: Bryja
authors.forename: Ola
authors.initials: O
authors.lastname: Hermanson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002831:Choroid Plexus / Q000166:cytology / Q000196:embryology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D000072261:Dishevelled Proteins; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D013687:Telencephalon / Q000166:cytology / Q000196:embryology*; D014157:Transcription Factors / Q000096:biosynthesis*; D015854:Up-Regulation / Q000502:physiology; D051153:Wnt Proteins / Q000096:biosynthesis*; D060508:Wnt3 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C525811:Bmp4 protein, rat; D055415:Bone Morphogenetic Protein 4; C539581:CXXC5 protein, rat; D003598:Cytoskeletal Proteins; D000072261:Dishevelled Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D051153:Wnt Proteins; D060508:Wnt3 Protein