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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Veröffentlicht in:Development (Cambridge) Jg. 143; H. 24; S. 4723
Hauptverfasser: Sima, Jian, Piao, Yulan, Chen, Yaohui, Schlessinger, David
Format: Journal Article
Sprache:Englisch
Veröffentlicht: England 15.12.2016
Schlagworte:
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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Abstract 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.
AbstractList 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.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.
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.
Author Piao, Yulan
Chen, Yaohui
Sima, Jian
Schlessinger, David
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Eda
Mouse
Proteolytic cleavage
Lrp6
Wnt
Meibomian gland
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References 18495521 - Cytokine Growth Factor Rev. 2008 Jun-Aug;19(3-4):219-30
22451941 - Proc Natl Acad Sci U S A. 2012 Apr 10;109(15):5744-9
15972955 - Am J Pathol. 2005 Jul;167(1):89-95
10559902 - Nat Cell Biol. 1999 Jul;1(3):158-64
15035989 - Cell. 2004 Mar 19;116(6):883-95
25249463 - Development. 2014 Oct;141(19):3752-60
15469841 - Dev Cell. 2004 Oct;7(4):525-34
20347428 - Mol Cell. 2010 Mar 26;37(6):865-78
18508042 - Dev Biol. 2008 Aug 1;320(1):60-71
11448771 - Curr Biol. 2001 Jun 26;11(12):951-61
9450748 - Nature. 1998 Jan 22;391(6665):357-62
12527209 - Gene. 2003 Jan 2;302(1-2):179-83
22733757 - Proc Natl Acad Sci U S A. 2012 Jul 10;109(28):11402-7
21984209 - Nat Struct Mol Biol. 2011 Oct 09;18(11):1204-10
15908424 - J Biol Chem. 2005 Jul 22;280(29):26770-5
21937108 - Placenta. 2011 Nov;32(11):877-84
10570958 - Gene. 1999 Oct 1;238(2):301-13
12699626 - Curr Biol. 2003 Apr 15;13(8):680-5
17081971 - Cell. 2006 Nov 3;127(3):469-80
15473860 - Annu Rev Cell Dev Biol. 2004;20:781-810
23209129 - Cold Spring Harb Perspect Biol. 2013 Feb 01;5(2):null
22000856 - Dev Cell. 2011 Nov 15;21(5):862-73
11357136 - Nature. 2001 May 17;411(6835):321-5
17143291 - Oncogene. 2006 Dec 4;25(57):7469-81
16382675 - J Investig Dermatol Symp Proc. 2005 Dec;10(3):247-51
19279724 - Organogenesis. 2008 Apr;4(2):123-33
12015971 - Dev Cell. 2002 May;2(5):643-53
19856966 - J Med Chem. 2009 Nov 26;52(22):6962-5
19619488 - Dev Cell. 2009 Jul;17(1):9-26
20856934 - PLoS One. 2010 Sep 13;5(9):e12682
17397822 - Dev Biol. 2007 May 15;305(2):498-507
25030692 - Genes Dev. 2014 Jul 15;28(14):1517-32
11433302 - Nat Cell Biol. 2001 Jul;3(7):683-6
25455110 - Trends Cell Biol. 2015 Feb;25(2):92-9
17082421 - Science. 2006 Dec 1;314(5804):1447-50
20093360 - J Biol Chem. 2010 Mar 19;285(12):9172-9
17314969 - Nature. 2007 Feb 22;445(7130):834-42
11035039 - J Biol Chem. 2001 Jan 26;276(4):2668-77
19619491 - Dev Cell. 2009 Jul;17(1):49-61
15037317 - Mech Dev. 2004 Feb;121(2):157-71
20386733 - PLoS One. 2010 Apr 01;5(4):e10009
23085770 - Cold Spring Harb Perspect Biol. 2013 Mar 01;5(3):a015081
References_xml – reference: 9450748 - Nature. 1998 Jan 22;391(6665):357-62
– reference: 22733757 - Proc Natl Acad Sci U S A. 2012 Jul 10;109(28):11402-7
– reference: 11035039 - J Biol Chem. 2001 Jan 26;276(4):2668-77
– reference: 22451941 - Proc Natl Acad Sci U S A. 2012 Apr 10;109(15):5744-9
– reference: 25455110 - Trends Cell Biol. 2015 Feb;25(2):92-9
– reference: 20347428 - Mol Cell. 2010 Mar 26;37(6):865-78
– reference: 10570958 - Gene. 1999 Oct 1;238(2):301-13
– reference: 17397822 - Dev Biol. 2007 May 15;305(2):498-507
– reference: 17082421 - Science. 2006 Dec 1;314(5804):1447-50
– reference: 17081971 - Cell. 2006 Nov 3;127(3):469-80
– reference: 18495521 - Cytokine Growth Factor Rev. 2008 Jun-Aug;19(3-4):219-30
– reference: 15469841 - Dev Cell. 2004 Oct;7(4):525-34
– reference: 23209129 - Cold Spring Harb Perspect Biol. 2013 Feb 01;5(2):null
– reference: 15908424 - J Biol Chem. 2005 Jul 22;280(29):26770-5
– reference: 12699626 - Curr Biol. 2003 Apr 15;13(8):680-5
– reference: 21984209 - Nat Struct Mol Biol. 2011 Oct 09;18(11):1204-10
– reference: 19856966 - J Med Chem. 2009 Nov 26;52(22):6962-5
– reference: 15972955 - Am J Pathol. 2005 Jul;167(1):89-95
– reference: 11357136 - Nature. 2001 May 17;411(6835):321-5
– reference: 15037317 - Mech Dev. 2004 Feb;121(2):157-71
– reference: 15473860 - Annu Rev Cell Dev Biol. 2004;20:781-810
– reference: 12015971 - Dev Cell. 2002 May;2(5):643-53
– reference: 20093360 - J Biol Chem. 2010 Mar 19;285(12):9172-9
– reference: 17143291 - Oncogene. 2006 Dec 4;25(57):7469-81
– reference: 20386733 - PLoS One. 2010 Apr 01;5(4):e10009
– reference: 22000856 - Dev Cell. 2011 Nov 15;21(5):862-73
– reference: 10559902 - Nat Cell Biol. 1999 Jul;1(3):158-64
– reference: 15035989 - Cell. 2004 Mar 19;116(6):883-95
– reference: 18508042 - Dev Biol. 2008 Aug 1;320(1):60-71
– reference: 21937108 - Placenta. 2011 Nov;32(11):877-84
– reference: 19279724 - Organogenesis. 2008 Apr;4(2):123-33
– reference: 25249463 - Development. 2014 Oct;141(19):3752-60
– reference: 11433302 - Nat Cell Biol. 2001 Jul;3(7):683-6
– reference: 16382675 - J Investig Dermatol Symp Proc. 2005 Dec;10(3):247-51
– reference: 25030692 - Genes Dev. 2014 Jul 15;28(14):1517-32
– reference: 12527209 - Gene. 2003 Jan 2;302(1-2):179-83
– reference: 19619488 - Dev Cell. 2009 Jul;17(1):9-26
– reference: 20856934 - PLoS One. 2010 Sep 13;5(9):e12682
– reference: 19619491 - Dev Cell. 2009 Jul;17(1):49-61
– reference: 11448771 - Curr Biol. 2001 Jun 26;11(12):951-61
– reference: 23085770 - Cold Spring Harb Perspect Biol. 2013 Mar 01;5(3):a015081
– reference: 17314969 - Nature. 2007 Feb 22;445(7130):834-42
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Snippet Secreted Dickkopf (Dkk) proteins are major Wnt pathway modulators during organ development. Dkk1 has been widely studied and acts as a general Wnt inhibitor....
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SubjectTerms 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
Title Molecular dynamics of Dkk4 modulates Wnt action and regulates meibomian gland development
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