BMP antagonism is required in both the node and lateral plate mesoderm for mammalian left-right axis establishment

Abstract

In mouse, left-right (L-R) patterning depends on asymmetric expression of Nodal around the node, leading to Nodal expression specifically in the left lateral plate mesoderm (LPM). Bone morphogenetic protein (BMP) signaling is also involved, but the mechanistic relationship with Nodal expression remains unclear. We find that BMP signal transduction is higher in the right LPM, although Bmp4, which is required for L-R patterning, is expressed symmetrically. By contrast, the BMP antagonists noggin (Nog) and chordin (Chrd) are expressed at higher levels in the left LPM. In Chrd;Nog double mutants, BMP signaling is elevated on both sides, whereas Nodal expression is absent. Ectopic expression of Nog in the left LPM of double mutants restores Nodal expression. Ectopic Bmp4 expression in the left LPM of wild-type embryos represses Nodal transcription, whereas ectopic Nog in the right LPM leads to inappropriate Nodal expression. These data indicate that chordin and noggin function to limit BMP signaling in the left LPM, thereby derepressing Nodal expression. In the node, they promote peripheral Nodal expression and proper node morphology, potentially in concert with Notch signaling. These results indicate that BMP antagonism is required in both the node and LPM to facilitate L-R axis establishment in the mammalian embryo.

BMP/SMAD1 signaling sets a threshold for the left/right pathway in lateral plate mesoderm and limits availability of SMAD4

“…BMPs have been implicated in LR patterning, but data on their precise roles have been highly contradictory, with results varying both within and between developmental models Yokouchi et al 1999;Monsoro-Burq and Le Douarin 2001;Fujiwara et al 2002;Piedra and Ros 2002;Schlange et al 2002;Kishigami et al 2004;Zhu and Scott 2004;Chocron et al 2007;Mine et al 2008). This is in part because BMPs act at distinct times and in distinct spatial domains to influence laterality (Kishigami et al 2004).…”

“…This is in part because BMPs act at distinct times and in distinct spatial domains to influence laterality (Kishigami et al 2004). Genetic data have provided evidence that BMPs need to be inhibited for correct left-sided Nodal expression (Chang et al 2000(Chang et al , 2002Constam and Robertson 2000;Kishigami et al 2004;Mine et al 2008). However, the spatial and temporal requirement for BMP signaling in these models could not be precisely established as both the node and the LPM were affected, casting doubt on the integrity of nodal flow and/or the midline barrier.…”

Cerberus functions as a BMP agonist to synergistically induce nodal expression during left–right axis determination in the chick embryo

“…In a recent study, it was demonstrated that BMP antagonism is required for the L-R asymmetrical Nodal expression in the mouse LPM (Mine et al, 2008). This distinct molecular regulation of Nodal expression between the chick and mouse could be attributed to species difference, as it has been demonstrated previously for the role of Shh and Fgf8 in the determination of L-R axis determination (Myers and Martin, 1999).…”

“…In mice, although studies argued for a possible role for BMP signaling in the regulation of Nodal expression in the LPM (Fujiwara et al, 2002), many studies pointed to a negative role for BMP in Nodal induction (Chang et al, 2000;Kishigami et al, 2004;Mine et al, 2008). In a recent study, it was demonstrated that BMP antagonism is required for the L-R asymmetrical Nodal expression in the mouse LPM (Mine et al, 2008).…”

“…In the mouse, the role of BMP in regulating Nodal in the LPM has also been controversial. In studies using mouse embryos, BMP activities are shown to exert either positive or negative roles, depending on genetically modifed mouse lines that were analyzed (Chang et al, 2000;Fujiwara et al, 2002;Kishigami et al, 2004;Mine et al, 2008).…”