Molecular dynamics of Dkk4 modulates Wnt action and regulates meibomian gland development

Secreted Dickkopf (Dkk) proteins are major Wnt pathway modulators during organ development. Dkk1 has been widely studied and acts as a general Wnt inhibitor. However, the molecular function of other Dkks remains largely unknown. Here, we show that Dkk4 selectively inhibits a subset of Wnts, but is f...

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Vydáno v:Development (Cambridge) Ročník 143; číslo 24; s. 4723
Hlavní autoři: Sima, Jian, Piao, Yulan, Chen, Yaohui, Schlessinger, David
Médium: Journal Article
Jazyk:angličtina
Vydáno: England 15.12.2016
Témata:
Animals
Cell Line
HEK293 Cells
Humans
Intercellular Signaling Peptides and Proteins - metabolism
Low Density Lipoprotein Receptor-Related Protein-6 - metabolism
Meibomian Glands - growth & development
Mice
Mice, Inbred C57BL
Mice, Transgenic
Protein Binding
Skin - metabolism
Wnt Proteins - antagonists & inhibitors
Wnt Proteins - metabolism
Wnt Signaling Pathway - physiology
Dkk4
Eda
Mouse
Proteolytic cleavage
Lrp6
Wnt
Meibomian gland
ISSN:1477-9129, 1477-9129
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Popis
Shrnutí:Secreted Dickkopf (Dkk) proteins are major Wnt pathway modulators during organ development. Dkk1 has been widely studied and acts as a general Wnt inhibitor. However, the molecular function of other Dkks remains largely unknown. Here, we show that Dkk4 selectively inhibits a subset of Wnts, but is further inactivated by proteolytic cleavage. Meibomian gland (MG) formation is employed as a model where Dkk4 and its Wnt targets are expressed. Skin-specific expression of Dkk4 arrests MG growth at early germ phase, which is similar to that observed in Eda-ablated Tabby mice. Consistent with transient Dkk4 action, intact Dkk4 inhibits MG extension but the cleaved form progressively increases during MG development with a concomitant upswing in Wnt activity. Furthermore, both Dkk4 and its receptor (and Wnt co-receptor) Lrp6 are direct Eda targets during MG induction. In cell and organotypic cultures, Dkk4 inhibition is eliminated by elevation of Lrp6. Also, Lrp6 upregulation restores MG formation in Tabby mice. Thus, the dynamic state of Dkk4 itself and its interaction with Lrp6 modulates Wnt function during MG development, with a novel limitation of Dkk4 action by proteolytic cleavage.
Bibliografie:ObjectType-Article-1
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content type line 23
ISSN:1477-9129
1477-9129
DOI:10.1242/dev.143909