PUBLICATION

A Huluwa phosphorylation switch regulates embryonic axis induction

Authors

Li, Y., Yan, Y., Gong, B., Zheng, Q., Zhou, H., Sun, J., Li, M., Wang, Z., Li, Y., Wan, Y., Chen, W., Qi, S., Mo, X., Meng, A., Xiang, B., Chen, J.

ID

ZDB-PUB-241121-3

Date

2024

Source

Nature communications 15: 1002810028 (Journal)

Registered Authors

Chen, Jing, Gong, Bo, Meng, Anming, Mo, Xianming

Keywords

none

MeSH Terms

Embryo, Nonmammalian/metabolism
Zebrafish*/embryology
Zebrafish*/genetics
Zebrafish*/metabolism
Xenopus Proteins/genetics
Xenopus Proteins/metabolism
Animals
Body Patterning/genetics
beta Catenin*/genetics
beta Catenin*/metabolism
Axin Protein/genetics
Axin Protein/metabolism
Phosphorylation
Signal Transduction
Mutation
Gene Expression Regulation, Developmental
Tankyrases/genetics
Tankyrases/metabolism
Cyclin-Dependent Kinases/genetics
Cyclin-Dependent Kinases/metabolism
Zebrafish Proteins*/genetics
Zebrafish Proteins*/metabolism

PubMed

39562571 Full text @ Nat. Commun.

Abstract

Embryonic axis formation is essential for patterning and morphogenesis in vertebrates and is tightly regulated by the dorsal organizer. Previously, we demonstrated that maternally derived Huluwa (Hwa) acts as a dorsal determinant, dictating axis formation by activating β-catenin signaling in zebrafish and Xenopus. However, the mechanism of activation and fine regulation of the Hwa protein remains unclear. Through candidate screening we identified a mutation at Ser168 in the PPNSP motif of Hwa that dramatically abolishes its axis-inducing activity. Mechanistically, mutating the Ser168 residue reduced its binding affinity to Tankyrase 1/2 and the degradation of the Axin protein, weakening β-catenin signaling activation. We confirmed that Ser168 is phosphorylated and that phosphorylation increases Hwa activity in β-catenin signaling and axis induction. Several kinases including Cdk16, Cdk2, and GSK3β, were found to enhance Ser168 phosphorylation in vitro and in vivo. Both dominant-negative Cdk16 expression and pHwa (Ser168) antibody treatment reduce Hwa function. Lastly, a knock-in allele mutating Ser168 to alanine resulted in embryos lacking body axes, demonstrating that Ser168 is essential to axis formation. In summary, Ser168 acts as a phosphorylation switch in Hwa/β-catenin signaling for embryonic axis induction, regulated by multiple kinases.

Genes / Markers

Figures