Transgelin-expressing myofibroblasts orchestrate ventral midline closure through TGFβ signalling.

Bashar Aldeiri,Urmas Roostalu,Alessandra Albertini,Antonino Morabito,Giulio Cossu,Jason Wong

doi:10.1242/dev.152843

Abstract

Ventral body wall (VBW) defects are among the most common congenital malformations, yet their embryonic origin and underlying molecular mechanisms remain poorly characterised. Transforming growth factor beta (TGFβ) signalling is essential for VBW closure, but the responding cells are not known. Here, we identify in mouse a population of migratory myofibroblasts at the leading edge of the closing VBW that express the actin-binding protein transgelin (TAGLN) and TGFβ receptor (TGFβR). These cells respond to a temporally regulated TGFβ2 gradient originating from the epithelium of the primary body wall. Targeted elimination of TGFβR2 in TAGLN+ cells impairs midline closure and prevents the correct subsequent patterning of the musculature and skeletal components. Remarkably, deletion of Tgfbr2 in myogenic or chondrogenic progenitor cells does not manifest in midline defects. Our results indicate a pivotal significance of VBW myofibroblasts in orchestrating ventral midline closure by mediating the response to the TGFβ gradient. Altogether, our data enable us to distinguish highly regulated epithelial-mesenchymal signalling and successive cellular migration events in VBW closure that explain early morphological changes underlying the development of congenital VBW defects.

Highlights

Abdominal wall defects are common in humans and cause significant morbidity and mortality (Wilson and Johnson, 2004)
We show that ventral body wall (VBW) closure relies on polarised migration of TAGLN+ myofibroblasts towards a Transforming growth factor β (TGFβ) morphogen gradient originating from the epithelium of the primary body wall
In order to follow the fate of TAGLN-expressing cells in primary body wall, we crossed the Tagln-Cre mouse strain to the Rosa26-NGZ [Gt (ROSA)26Sortm1(CAG-lacZ,EGFP)Glh] reporter strain and performed whole-mount β-galactosidase staining at various embryonic stages

Summary

Introduction

Abdominal wall defects are common in humans and cause significant morbidity and mortality (Wilson and Johnson, 2004) They show a variety of phenotypic abnormalities that differ in their anatomy, and in their mode of development, organ involvement and short- and long-term outcomes (Carnaghan et al, 2013; Christison-Lagay et al, 2011; Gamba and Midrio, 2014; Sadler, 2010; Sadler and Feldkamp, 2008). Starting from ∼E12, differentiated secondary mesenchymal components arising laterally from the flanks follow the primary body wall. This later cellular migration process continues through late embryonic stages, and complete migration and fusion of the secondary body wall elements is fully achieved by E15.5 in the thorax and E16.5 in the abdomen (Kaufman and Bard, 1999). The cellular and morphogenetic components of the epithelial-mesenchymal pathway in ventral midline closure remain largely obscure

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