Loss of AP-2α impacts multiple aspects of ventral body wall development and closure

Abstract

Human birth defects involving the ventral body wall are common, yet little is known about the mechanism of body wall closure in mammals. The AP-2alpha transcription factor knock-out mouse provides an exceptional tool to understand this particular pathology, since it has one of the most severe ventral body wall closure defects, thoracoabdominoschisis. To gain insight into the complex morphological events responsible for body wall closure, we have studied this developmental process in AP-2alpha knock-out mice. Several tissues involved in normal ventral body wall closure are defective in the absence of AP-2alpha, including those associated with the primary body wall, the umbilical ring, and the mesoderm of the secondary body wall. These defects, coupled with the expression pattern of AP-2alpha, suggest that AP-2alpha is involved in multiple developmental mechanisms directing the morphogenesis of the ventral body wall, including cell migration, differentiation, and death. There is a failure of migration and fusion of the body folds at the umbilical ring, as well as in the formation and migration of the abdominal bands and ventral musculature. Furthermore, the mechanism of cell deposition at the umbilical ring is disturbed. Consequently, the mesodermal compartment of the body wall is underdeveloped. We also suggest that AP-2alpha is required for signaling from the surface ectoderm to the underlying mesoderm for proper development and closure of the ventral body wall. These findings provide a fundamental understanding of how AP-2alpha functions in the closure of the ventral body wall, as well as offer insight into related human birth defects.

Morphogenesis of the Manubrium of Sternum in Human Embryos: A New Concept

“…Manley et al (2001) demonstrated an unsuccessful fusion of the bilateral anlagen of the sternum in hoxb4 mutant mice. Likewise, in AP-2alpha transcription factor knock-out mice, the unsuccessful midline fusion occurs because the abdominal band (rectus muscle anlagen) as well as the covering abdominal epidermis fails to develop (Brewer and Williams, 2004). These references suggest that a midline fusion of the sternal body is regulated by somite derivatives.…”

Ventral abdominal wall dysmorphogenesis of Msx1/Msx2 double‐mutant mice

“…It has been known that Hox genes could be regulated by retinoic acid (RA) indicated by various experimental systems (Kessel and Gruss, 1990;Yashiro et al, 2004). As for another retinoic acid-inducible transcription factor, Ap-2, the AP-2␣ knockout mice also exhibit severe ventral body wall closure defects (Schorle et al, 1996;Zhang et al, 1996;Brewer and Williams, 2004b). These results raise questions about possible regulatory cascades among such genes for ventral body wall formation.…”

Molecular genetic cascades for external genitalia formation: An emerging organogenesis program

“…It has thus been speculated that GT development requires correct adjacent tissue differentiation, such as lower body wall formation. Abnormal lower body wall formation associated with bladder/cloaca extrophy often simultaneously displays genital abnormalities such as the upper GT defects, and epispadias (Zhang et al, 1996;Brewer and Williams, 2004;Ogi et al, 2005;Haraguchi et al, unpublished results). In relation with such phenotypes, the presence or absence of cell migration between the umbilical region (later the lower body wall) and the (upper) GT bud requires further analyses.…”