Ventral body wall closure: Mechanistic insights from mouse models and translation to human pathology

Abstract

The ventral body wall (VBW) that encloses the thoracic and abdominal cavities arises by extensive cell movements and morphogenetic changes during embryonic development. These morphogenetic processes include embryonic folding generating the primary body wall; the initial ventral cover of the embryo, followed by directed mesodermal cell migrations, contributing to the secondary body wall. Clinical anomalies in VBW development affect approximately 1 in 3000 live births. However, the cell interactions and critical cellular behaviors that control VBW development remain little understood. Here, we describe the embryonic origins of the VBW, the cellular and morphogenetic processes, and key genes, that are essential for VBW development. We also provide a clinical overview of VBW anomalies, together with environmental and genetic influences, and discuss the insight gained from over 70 mouse models that exhibit VBW defects, and their relevance, with respect to human pathology. In doing so we propose a phenotypic framework for researchers in the field which takes into account the clinical picture. We also highlight cases where there is a current paucity of mouse models for particular clinical defects and key gaps in knowledge about embryonic VBW development that need to be addressed to further understand mechanisms of human VBW pathologies.

Keywords: bladder or cloacal exstrophy; ectopia cordis; exomphalos; myofibroblasts; thoracoabdominoschisis; ventral body wall development.

FIGURE 1

Ventral body wall folding and the contribution of the paraxial and lateral plate mesoderm. (A–C) Progression of embryonic folding to generate the primary body wall from the early gastrula stage (A, A′), to later developmental stages, B, and then C. The stages shown are after embryo turning and model VBW closure in humans, mouse and chicks. In embryonic mice, Gata4, Furin, Hand1/2 control, the step shown in (A), Pitx2 the step shown in (B), and Six5/6 the stage shown in (C). (A) A lateral view while (A′, B, C) are transverse sections. The ectoderm is continuous with the amnion and the endoderm is continuous with the yolk sac. The amniotic sac/cavity initially lies above the embryo (A). The embryo folds laterally and along the cranial‐caudal axes such that the splanchnopleure is ultimately located in the center of the embryo as a blind ended tube. The somatopleure folds around to enclose the VBW. This somatopleure folding also brings the amnion around the embryo such that the amniotic sac now surrounds the entire embryo. (B, C) * demarcates the position of connection to amnion. (D, E) Schematics of the contribution of the paraxial mesoderm and LPM to the thoracic and abdominal ventral body wall, respectively, based on fate mapping studies in the mouse. The paraxial/LPM contribution varies between species (see Section 3.5) and although not proven, the mouse embryo is anticipated to more closely model human development compared to the chick. The distal intercostal muscles move just ahead of the ribs and become encapsulated by LPM., , Cranial‐caudal and dorso‐ventral axes are indicated. Block arrows indicate the direction of folding. AIP, anterior intestinal portal; EO, external oblique muscle, IO, internal oblique muscle, PIP, posterior intestinal portal. Tr, transversus abdominis muscle, Re, rectus abdominis muscle. Schematic (D) shows the human anatomy, panniculus carnosus muscle of mouse embryo is not shown. Outline for (B) and (D, E) based on Beddington and Robertson and Scaal, respectively.

FIGURE 2

Development of the secondary body wall. (A) Frontal, (B) semi‐lateral, and (C) transverse views of the mouse developing VBW at stages E12.5 (A, B) and E13.5 (C). The leading edge of the SBW (dark pink) followed by the adjacent tissue invades the PBW. The leading edge contains myofibroblasts that are essential for VBW closure and is ahead of the developing ribs/musculature and innervation which arise from the paraxial mesoderm and neuroectoderm, respectively. In the thoracic SBW, the leading edge also contains the mesosternal precursors. Bracket in (B) indicates SBW. The umbilical ring (UR) is the point of transient physiological herniation of the midgut: Here, a mesodermal layer separates the abdominal cavity of the embryo from the umbilical cord. Block arrows indicate the direction of cell movement. Secreted signals from the PBW control development of both the PBW and SBW. Genes expressed within the leading edge are also essential for advancement of the SBW and VBW closure. Dashed line in (C) indicates boundary between PBW and SBW. PBW, primary body wall, SBW secondary body. Outline for (A) and (C) based on Mao et al. and Nichol et al., respectively.