Cdo suppresses canonical Wnt signalling via interaction with Lrp6 thereby promoting neuronal differentiation

• Published in: Nature communications Vol. 5; no. 1; p. 5455
• Main Authors: Jeong, Myong-Ho, Ho, Seok-Man, Vuong, Tuan Anh, Jo, Shin-Bum, Liu, Guizhong, Aaronson, Stuart A., Leem, Young-Eun, Kang, Jong-Sun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.11.2014; Nature Publishing Group
• Subjects: 13; 13/1; 13/100; 13/109; 13/89; 13/95; 14; 14/1; 14/19; 14/32; 631/136/368; 631/378/2571; 631/80/86; 96; Animals; Axin Protein - metabolism; beta Catenin - metabolism; Cell Differentiation; Cysteine Dioxygenase - metabolism; Embryo, Mammalian; Eye Proteins - metabolism; Gene Expression Regulation, Developmental; Hedgehog Proteins - metabolism; Homeodomain Proteins - metabolism; Humanities and Social Sciences; Kruppel-Like Transcription Factors - metabolism; Low Density Lipoprotein Receptor-Related Protein-6 - metabolism; Mice; multidisciplinary; Nerve Tissue Proteins - metabolism; Neurogenesis; Neurons - cytology; Neurons - metabolism; Paired Box Transcription Factors - metabolism; PAX6 Transcription Factor; Repressor Proteins - metabolism; Science; Science (multidisciplinary); Wnt Proteins - metabolism; Wnt Signaling Pathway; Zinc Finger Protein Gli3
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms6455

Canonical Wnt signalling regulates expansion of neural progenitors and functions as a dorsalizing signal in the developing forebrain. In contrast, the multifunctional co-receptor Cdo promotes neuronal differentiation and is important for the function of the ventralizing signal, Shh. Here we show that Cdo negatively regulates Wnt signalling during neurogenesis. Wnt signalling is enhanced in Cdo-deficient cells, leading to impaired neuronal differentiation. The ectodomains of Cdo and Lrp6 interact via the Ig2 repeat of Cdo and the LDLR repeats of Lrp6, and the Cdo Ig2 repeat is necessary for Cdo-dependent Wnt inhibition. Furthermore, the Cdo-deficient dorsal forebrain displays stronger Wnt signalling activity, increased cell proliferation and enhanced expression of the dorsal markers and Wnt targets, Pax6, Gli3, Axin2. Therefore, in addition to promoting ventral central nervous system cell fates with Shh, Cdo promotes neuronal differentiation by suppression of Wnt signalling and provides a direct link between two major dorsoventral morphogenetic signalling pathways. Cdo regulates early forebrain development as a co-receptor of the morphogen Shh and is required for full activation of Shh signalling. Here the authors show that Cdo interacts with the Wnt co-receptor Lrp6, thereby inhibits Wnt signalling and promotes neuronal differentiation.