Control of neural crest induction by MarvelD3-mediated attenuation of JNK signalling

Karl Matter,Shin-Ichi Ohnuma,Noriaki Sasai,Maria S Balda,Barbara Vacca,Elena Sanchez-Heras,Sophie L Busson,Emily Steed,Roberto Mayor

doi:10.1038/s41598-018-19579-5

Abstract

Tight junctions are required for the formation of tissue barriers and function as suppressors of signalling mechanisms that control gene expression and cell behaviour; however, little is known about the physiological and developmental importance of such signalling functions. Here, we demonstrate that depletion of MarvelD3, a transmembrane protein of tight junctions, disrupts neural crest formation and, consequently, development of neural crest-derived tissues during Xenopus embryogenesis. Using embryos and explant cultures combined with a small molecule inhibitor or mutant mRNAs, we show that MarvelD3 is required to attenuate JNK signalling during neural crest induction and that inhibition of JNK pathway activation is sufficient to rescue the phenotype induced by MarvelD3 depletion. Direct JNK stimulation disrupts neural crest development, supporting the importance of negative regulation of JNK. Our data identify the junctional protein MarvelD3 as an essential regulator of early vertebrate development and neural crest induction and, thereby, link tight junctions to the control and timing of JNK signalling during early development.

Highlights

Tight junctions are composed of a large number of transmembrane and cytoplasmic plaque proteins
We found that MarvelD3 regulates eye morphogenesis in Xenopus laevis[13]
As we previously found that reduced expression of MarvelD3 in vitro stimulates JNK signalling and cell migration[10], we asked whether MarvelD3 depletion leads to precocious activation of JNK during neural crest induction

Summary

Introduction

Tight junctions are composed of a large number of transmembrane and cytoplasmic plaque proteins. While the junctional MARVEL domain proteins may modulate junctional permeability properties, they are thought to function mostly as regulators of tight junctions or components of signalling mechanisms by which tight junctions signal to the cell interior[6,9,10]. The importance of the MARVEL domain proteins as well as other tight junction transmembrane components for the regulation of signalling mechanisms in vivo and the physiological relevance of such processes is unclear. We further demonstrate that the underlying mechanism is attenuation of JNK signalling, identifying an unexpected importance of suppression of JNK to enable normal neural crest induction and demonstrating the physiological relevance of tight junction proteins as suppressors of intracellular signalling

Methods

Results

Conclusion