XB-ART-34623Development May 1, 2005; 132 (10): 2489-99.
Sirenomelia in Bmp7 and Tsg compound mutant mice: requirement for Bmp signaling in the development of ventral posterior mesoderm.
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.
PubMed ID: 15843411
Article link: Development
Genes referenced: bmp4 bmp7.1 bmp7.2 chrd.1 fgf8 myod1 otx2 shh szl tbxt twsg1
Morpholinos: bmp7.2 MO1 twsg1 MO1 twsg1 MO2
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|Fig. 3. Tsg and Bmp7 cooperate in ventral development in Xenopus embryos. (A,F,K,P) Control and morpholino-injected embryos at stage 12 hybridized with sizzled probe. Expression of sizzled is reduced in Bmp7-MO- or Tsg-MO-injected embryos and almost completely lost in the Bmp7-MO/Tsg-MO-injected embryos. (B,G,L,Q) Expression of Otx2 in injected embryos at stage 13; there is an increase in Bmp7-MO/Tsg-MO-injected embryos. (C,H,M,R) Embryos at stage 18 hybridized with Otx2 and Myod1 probes. The expansion of Otx2 regulates and is no longer seen at this stage. (D,E,I,J,N,O,S,T) Phenotypes of morpholino-injected embryos at (D,I,N,S) stage 39 (2 day) and (E,J,O,T) stage 42 (3 day). Bmp7-MO-injected embryos have a reduced ventral fin (arrowhead); Tsg-MO-injected embryos have a bent tail and reduction of ventral fin. Co-injection of Bmp7-MO and Tsg-MO synergize, causing a severe loss of ventral fin (arrow in S) and at later stages truncation of the entire tail region (T).|
|Fig. 7. Analysis of the sirenomelia phenotype. (A,B) Side view of 9.5 dpc wild-type and mutant embryos hybridized with Bmp4 probe. (A′,B′) Ventral views of hindlimb bud region of embryos shown in A and B, respectively; the tail has been excised. In the mutant, expression of Bmp4 in the future hindlimb bud mesoderm (hb) forms a transverse horizontal domain instead of two lateral ones on the right (rhb) and left (lhb) hindlimb buds seen in the wild type. (C,D) Side view of 10.5 dpc embryos hybridized with Fgf8 probe, marking the apical ectodermal ridge (aer). (C′,D′) Ventral views of hindlimb bud region of embryos shown in C and D, respectively. In the mutant, the aer expression domain of Fgf8 adopts a horseshoe-like shape, with the two aer regions meeting posteriorly instead of forming two lateral arches. (E,F) Side view of 10.5 dpc embryos hybridized with sonic hedgehog (Shh) probe. (E′,F′) Ventral views of hindlimb bud region at higher magnification. Expression of Shh in the zone of polarizing activity (zpa) is not yet detected, and hindgut (hg) staining is reduced in the mutant. (G,H) Side view of 9.5 dpc embryos hybridized with brachyury probe. (G′,H′) Higher magnification of tail region of embryos stained for brachyury. Staining of tail bud mesoderm (tbm) is decreased ventrally in the mutant; note the abnormal indentation (black arrow) and narrowing of the tail in the mutant. no, node; vm, ventral mesoderm.|