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Proc Natl Acad Sci U S A 2018 Sep 25;11539:E9135-E9144. doi: 10.1073/pnas.1812117115.
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Bighead is a Wnt antagonist secreted by the Xenopus Spemann organizer that promotes Lrp6 endocytosis.

Ding Y , Colozza G , Sosa EA , Moriyama Y , Rundle S , Salwinski L , De Robertis EM .

The Xenopus laevis embryo has been subjected to almost saturating screens for molecules specifically expressed in dorsal Spemann organizer tissue. In this study, we performed high-throughput RNA sequencing of ectodermal explants, called animal caps, which normally give rise to epidermis. We analyzed dissociated animal cap cells that, through sustained activation of MAPK, differentiate into neural tissue. We also microinjected mRNAs for Cerberus, Chordin, FGF8, BMP4, Wnt8, and Xnr2, which induce neural or other germ layer differentiations. The searchable database provided here represents a valuable resource for the early vertebrate cell differentiation. These analyses resulted in the identification of a gene present in frog and fish, which we call Bighead. Surprisingly, at gastrula, it was expressed in the Spemann organizer and endoderm, rather than in ectoderm as we expected. Despite the plethora of genes already mined from Spemann organizer tissue, Bighead encodes a secreted protein that proved to be a potent inhibitor of Wnt signaling in a number of embryological and cultured cell signaling assays. Overexpression of Bighead resulted in large head structures very similar to those of the well-known Wnt antagonists Dkk1 and Frzb-1. Knockdown of Bighead with specific antisense morpholinos resulted in embryos with reduced head structures, due to increased Wnt signaling. Bighead protein bound specifically to the Wnt coreceptor lipoprotein receptor-related protein 6 (Lrp6), leading to its removal from the cell surface. Bighead joins two other Wnt antagonists, Dkk1 and Angptl4, which function as Lrp6 endocytosis regulators. These results suggest that endocytosis plays a crucial role in Wnt signaling.

PubMed ID: 30209221
PMC ID: PMC6166843
Article link: Proc Natl Acad Sci U S A
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: angptl4 bmp4 cer1 chrd chrd.2 ctnnb1 ctrl dkk1 egr2 en2 fgf8 frzb h2ac1 h2bc14 lefty lrp6 mapk1 mstn.1 nhs nodal2 nodal3.1 nodal3.2 otx2 pkdcc.1 rax sfrp2 sia1 sox2 tf wnt3a wnt8a XB5731801 XB5848002 zic1 zic3 zic4
GO keywords: Wnt signaling pathway [+]
Morpholinos: LOC100494211 MO1 LOC100494211 MO2

GEO Series: GSE106320: Xenbase,  NCBI

Article Images: [+] show captions
References [+] :
Acebron, Mitotic wnt signaling promotes protein stabilization and regulates cell size. 2014, Pubmed