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The Lee Lab at Vanderbilt

Developmental regulation of Wnt signaling by Nagk and the UDP-GlcNAc salvage pathway.

AUTHORS

Neitzel LR , Spencer ZT , Nayak A , Cselenyi CS , Benchabane H , Youngblood CQ , Zouaoui A , Ng V , Stephens L , Hann T , Patton JG , Robbins D , Ahmed Y , Lee E . Mechanism of Development. 2019 ; 156(). 20-31

ABSTRACT

In a screen for human kinases that regulate Xenopus laevis embryogenesis, we identified Nagk and other components of the UDP-GlcNAc glycosylation salvage pathway as regulators of anteroposterior patterning and Wnt signaling. We find that the salvage pathwaydoes not affect other major embryonic signaling pathways (Fgf, TGFβ, Notch, or Shh), thereby demonstrating specificity for Wntsignaling. We show that the role of the salvage pathway in Wnt signaling is evolutionarily conserved in zebrafish and Drosophila. Finally, we show that GlcNAc is essential for the growth of intestinal enteroids, which are highly dependent on Wnt signaling for growth and maintenance. We propose that the Wnt pathway is sensitive to alterations in the glycosylation state of a cell and acts as a nutritional sensor in order to couple growth/proliferation with its metabolic status. We also propose that the clinical manifestations observed in congenital disorders of glycosylation (CDG) in humans may be due, in part, to their effects on Wnt signaling during development.