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Development 2008 May 01;13510:1813-22. doi: 10.1242/dev.019323.
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Regulation of TGF-(beta) signalling by N-acetylgalactosaminyltransferase-like 1.

Herr P , Korniychuk G , Yamamoto Y , Grubisic K , Oelgeschläger M .

The TGF-beta superfamily of secreted signalling molecules plays a pivotal role in the regulation of early embryogenesis, organogenesis and adult tissue homeostasis. Here we report the identification of Xenopus N-acetylgalactosaminyltransferase-like 1 (xGalntl-1) as a novel important regulator of TGF-beta signalling. N-acetylgalactosaminyltransferases mediate the first step of mucin-type glycosylation, adding N-acetylgalactose to serine or threonine side chains. xGalntl-1 is expressed in the anterior mesoderm and neural crest territory at neurula stage, and in the anterior neural crest, notochord and the mediolateral spinal cord at tailbud stage. Inhibition of endogenous xGalntl-1 protein synthesis, using specific morpholino oligomers, interfered with the formation of anterior neural crest, anterior notochord and the spinal cord. Xenopus and mammalian Galntl-1 inhibited Activin as well as BMP signalling in the early Xenopus embryo and in human HEK 293T cells. Gain- and loss-of-function experiments showed that xGalntl-1 interferes with the activity of the common TGF-beta type II receptor ActR-IIB in vivo. In addition, our biochemical data demonstrated that xGalntl-1 specifically interferes with the binding of ActR-IIB to Activin- and BMP-specific type I receptors. This inhibitory activity of xGalntl-1 was dependent on mucin-type glycosylation, as it was sensitive to the chemical inhibitor benzyl-GalNAc. These studies reveal an important role of a N-acetylgalactosaminyltransferase in the regulation of TGF-beta signalling. This novel regulatory mechanism is evolutionarily conserved and, thus, might provide a new paradigm for the regulation of TGF-beta signalling in vertebrates.

PubMed ID: 18417620
Article link: Development

Species referenced: Xenopus
Genes referenced: actl6a ag1 alk bmp4 bmpr1a bmpr1b chrd dlx5 fgf4 galnt14 galnt16 galnt2 gata1 msx1 myc myod1 ncam1 ncoa3 odc1 otx2 rax sia1 six3 smad1 smad2 snai1 snai2 tbxt ventx1.2 ventx2.2 wnt8a
Morpholinos: galnt16 MO1 galnt16 MO2

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