Sirenomelia inBmp7andTsgcompound mutant mice:requirement for Bmp signaling in the development of ventral posterior mesoderm

Abstract

Sirenomelia or mermaid-like phenotype is one of the principal human congenital malformations that can be traced back to the stage of gastrulation. Sirenomelia is characterized by the fusion of the two hindlimbs into a single one. In the mouse, sirens have been observed in crosses between specific strains and as the consequence of mutations that increase retinoic acid levels. We report that the loss of bone morphogenetic protein 7 (Bmp7) in combination with a half dose or complete loss of twisted gastrulation (Tsg)causes sirenomelia in the mouse. Tsg is a Bmp- and chordin-binding protein that has multiple effects on Bmp metabolism in the extracellular space; Bmp7 is one of many Bmps and is shown here to bind to Tsg. In Xenopus,co-injection of Tsg and Bmp7 morpholino oligonucleotides (MO) has a synergistic effect, greatly inhibiting formation of ventral mesoderm and ventral fin tissue. In the mouse, molecular marker studies indicate that the sirenomelia phenotype is associated with a defect in the formation of ventroposterior mesoderm. These experiments demonstrate that dorsoventral patterning of the mouse posterior mesoderm is regulated by Bmp signaling, as is the case in other vertebrates. Sirens result from a fusion of the hindlimb buds caused by a defect in the formation of ventral mesoderm.

Twisted Gastrulation Modulates Bone Morphogenetic Protein-induced Collagen II and X Expression in Chondrocytesin Vitroandin Vivo

“…In vitro, TSG has been shown to bind directly with its N-terminal domain to BMP-2 and -4 (28) but also to BMP-7 (57). In fact, loss of BMP-7 in combination with half-dose or complete loss of TSG caused fusion of legs (sirenomelia) in mice (57), and BMP-4/7 heterozygote mice develop minor defects in the rib cage and the distal part of the limbs (72), also suggesting a physiological link of TSG with BMP-7 signaling in cartilage development. However, the concentration gradient of BMP-7 in the growth plate chondrocytes was in the reverse order as compared with BMP-4.…”

Concerted involvement of Cdx/Hox genes and Wnt signaling in morphogenesis of the caudal neural tube and cloacal derivatives from the posterior growth zone

“…At later stages, after the posterior neuropore closes, the anterior primitive streak, node-streak border and node region become internalized and form the chordoneural hinge (CNH) (Gont et al, 1993;Wilson et al, 2009), whereas the rest of the primitive streak is curved along the ventral outer surface of the tailbud, becoming the ventral ectodermal ridge (VER). Mesoderm emergence from the VER, regulated by BMP (Ohta et al, 2007;Zakin et al, 2005), contributes some cells to the posterior tailbud until E9.5 (Ohta et al, 2007;Wilson and Beddington, 1996) and has completely ceased to do by E10.5. The trunk lateral mesoderm at axial levels of the uro-rectal septum therefore must be laid down from progenitors that have emerged from the posterior growth zone earlier than when cloacal septation takes place.…”

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

“…Bmp7 has also been recognized to be involved in epithelial-to-mesenchymal transition (EMT) during kidney development, and other developmental processes (Dudley et al, 1995(Dudley et al, , 1999Zeisberg et al, 2003). Bmp7 has also been reported to play an important role in the hindbrain, tooth, eye development, and skeletal patterning (Luo et al, 1995;Arkell et al, 1997;Godin et al, 1998;Zakin et al, 2005). In urogenital/reproductive systems, it functions in apoptotic regulation and the tissue remodeling of the oviduct (Monroe et al, 2000).…”

“…Another caudal phenotype elicited by the manipulation of early key developmental regulators could arise from the possible "reduction" of the cloacal field as the Sirenomelia phenotype displays hindlimb fusion and the ventral posterior embryonic dysgenesis known also as Mermaid Syndrome (Zakin et al, 2005). Sirenomelia is a human developmental cloacal malformation characterized by the fusion of both hindlimbs (Kampmeier, 1927;Hoornbeek, 1970).…”