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

Area of Science:

• Developmental biology
• Molecular signaling
• Organogenesis

Background:

• Secreted Dickkopf (Dkk) proteins regulate Wnt signaling, crucial for organ development.
• While Dkk1 is well-studied, the functions of other Dkk proteins, like Dkk4, are largely unknown.
• Meibomian gland (MG) formation serves as a model to investigate Dkk4's role.

Purpose of the Study:

• To elucidate the molecular function of Dkk4 in Wnt pathway modulation during MG development.
• To investigate the inactivation mechanism of Dkk4 via proteolytic cleavage.
• To understand the interaction between Dkk4, Lrp6, and the Eda pathway in MG formation.

Main Methods:

• Skin-specific Dkk4 expression in mouse models.
• Analysis of MG growth and Wnt activity.
• Cell and organotypic cultures.
• Investigation of Dkk4 and Lrp6 as Eda targets.

Main Results:

• Dkk4 expression arrests MG growth, mimicking Eda-deficient phenotypes.
• Intact Dkk4 inhibits MG extension, while cleaved Dkk4 increases with Wnt activity.
• Dkk4 and Lrp6 are direct Eda targets.
• Lrp6 upregulation rescues MG formation in Dkk4-inhibited and Eda-deficient models.

Conclusions:

• Dkk4 selectively inhibits a subset of Wnts and its function is modulated by proteolytic cleavage.
• The dynamic interplay between Dkk4 and Lrp6 regulates Wnt signaling during MG development.
• Proteolytic cleavage represents a novel mechanism limiting Dkk4 activity.