Genetic dissection of ventral folding morphogenesis in mouse: embryonic visceral endoderm-supplied BMP2 positions head and heart

Abstract

Ventral folding morphogenesis, a vital morphogenetic process in amniotes, mediates gut endoderm internalization, linear heart tube formation, ventral body wall closure and encasement of the fetus in extraembryonic membranes. Aberrant ventral folding morphogenesis underlies a number of birth defects, such as gastroschisis and ectopia cordis in human and misplacement of head and heart in mouse. Recent cell lineage-specific mouse mutant analyses identified the Bone Morphogenetic Protein (BMP) pathway and Anterior Visceral Endoderm (AVE) as key regulators of anterior ventral folding morphogenesis. Loss of BMP2 expression solely from embryonic visceral endoderm (EmVE) and the AVE blocks formation of foregut invagination, and simultaneously, aberrantly positions the heart anterior/dorsal to the head, suggesting a mechanistic link between foregut and head/heart morphogenesis.

Symmetric BMPs on the Developmental Road

“…Such observations emphasize that irregularities occurring during VFM (fifth week of human gestation) can result in severe structural defects later in development and at birth. As Arraf et al (2016) comment, this work, as well as that of others (Madabhushi and Lacy, 2011;Gavrilov and Lacy, 2013), points to a central role for BMP signaling in coordinating multiple events during VFM. Thus, future studies probing interactions between BMP and other key signaling pathways (SHH, WNT, FGF) promise a deeper understanding of tissue morphogenesis and organ positioning and of how perturbations during early embryogenesis will impact viability during fetal development and at birth.…”

“…Progress on this front is reported by Arraf et al (2016) The generation and development of the mesothelia occur in conjunction with ventral folding morphogenesis (VFM), a fundamental developmental process that in amniotes coordinates closure of the ventral body wall with formation of a linear heart tube, internalization of gut endoderm, and encasement of the fetus in extraembryonic membranes. The first phase of VFM takes place between the early head fold and 8-to 10-somite stages; during this phase, concurrent rostral-caudal and ventral-to-lateral tissue movements achieve formation of the foregut and hindgut pockets and placement of the head dorsal and anterior to the primitive heart tube (Gavrilov and Lacy, 2013). Arraf et al (2016) focus on the next phase of VFM, which proceeds in the midline region posterior to the heart and begins with the midgut endoderm residing on the external surface of the most ventral region of the embryo.…”

Nucleus to Mitochondria: Lost in Transcription, Found in Translation

“…Such observations emphasize that irregularities occurring during VFM (fifth week of human gestation) can result in severe structural defects later in development and at birth. As Arraf et al (2016) comment, this work, as well as that of others (Madabhushi and Lacy, 2011;Gavrilov and Lacy, 2013), points to a central role for BMP signaling in coordinating multiple events during VFM. Thus, future studies probing interactions between BMP and other key signaling pathways (SHH, WNT, FGF) promise a deeper understanding of tissue morphogenesis and organ positioning and of how perturbations during early embryogenesis will impact viability during fetal development and at birth.…”

Novel copy-number variants in a population-based investigation of classic heterotaxy

“…Affected embryos displayed various defects including an abnormal head-to-heart relationship, failure of cardiac looping, and lack of foregut invagination. 32 While animal studies support a link between bmp2/ bmp4 mutations and laterality disorders, we are the first to report a BMP2 deletion in association with a human heterotaxy phenotype.…”