NOGGIN-MEDIATED ANTAGONISM OF BMP SIGNALING IS REQUIRED FOR GROWTH AND PATTERNING OF THE NEURAL-TUBE AND SOMITE

Embryonic patterning in vertebrates is dependent upon the balance of i nductive signals and their specific antagonists. We show that Noggin, which encodes a bone morphogenetic protein (BMP) antagonist expressed in the node, notochord, and dorsal somite, is required for normal mous e development. Although Noggin has been implicated in neural induction , examination of null mutants in the mouse indicates that Noggin is no t essential for this process. However, Noggin is required for subseque nt growth and patterning of the neural tube. Early BMP-dependent dorsa l cell fates, the roof plate and neural crest, form in the absence of Noggin. However, there is a progressive loss of early, Sonic hedgehog (Shh)-dependent ventral cell fates despite the normal expression of Sh h in the notochord. Further, somite differentiation is deficient in bo th muscle and sclerotomal precursors. Addition of BMP2 or BMP4 to para xial mesoderm explants blocks Shh-mediated induction of Pax-1, a scler otomal marker, whereas addition of Noggin is sufficient to induce Pax- 1. Noggin and Shh induce Pax-1 synergistically. Use of protein kinase A stimulators blocks Shh-mediated induction of Pax-1, but not inductio n by Noggin, suggesting that induction is mediated by different pathwa ys. Together these data demonstrate that inhibition of BMP signaling b y axially secreted Noggin is an important requirement for normal patte rning of the vertebrate neural tube and somite.