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 inductive 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 mouse development. Although Noggin has been implicated in neural induction, examination of null mutants in the mouse indicates that Noggin is not essential for this process. However, Noggin is required for subsequent growth and patterning of the neural tube. Early BMP-dependent dorsal 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 Shh in the notochord. Further, somite differentiation is deficient in both muscle and sclerotomal precursors. Addition of BMP2 or BMP4 to paraxial mesoderm explants blocks Shh-mediated induction of Pax-1, a sclerotomal 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 induction by Noggin, suggesting that induction is mediated by different pathways. Together these data demonstrate that inhibition of BMP signaling by axially secreted Noggin is an important requirement for normal patterning of the vertebrate neural tube and somite.
McMahon
J A
JA
Department of Molecular and Cellular Biology, The Biolabs, Harvard University, Cambridge, Massachusetts 02138, USA.amcmahon.biosun.harvar d.edu
Takada
S
S
Zimmerman
L B
LB
Fan
C M
CM
Harland
R M
RM
McMahon
A P
AP
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D002352:Carrier Proteins; D002490:Central Nervous System / Q000196:embryology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology; D005314:Embryonic and Fetal Development / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D053823:Hedgehog Proteins; D006614:Hindlimb / Q000196:embryology; D017403:In Situ Hybridization; D008648:Mesoderm / Q000502:physiology; D051379:Mice / Q000196:embryology* / Q000235:genetics; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009024:Morphogenesis / Q000502:physiology; D009687:Nuclear Proteins / Q000502:physiology; D009924:Organ Culture Techniques; D051757:PAX5 Transcription Factor; D051761:Paired Box Transcription Factors; D011506:Proteins / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D019170:Somites / Q000502:physiology*; D013116:Spinal Cord / Q000196:embryology; D015534:Trans-Activators; D014157:Transcription Factors / Q000502:physiology; D016212:Transforming Growth Factor beta; D000099176:Noggin Protein
D015056:1-Methyl-3-isobutylxanthine; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D005576:Colforsin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D004268:DNA-Binding Proteins; D053823:Hedgehog Proteins; D009687:Nuclear Proteins; D051757:PAX5 Transcription Factor; D051761:Paired Box Transcription Factors; D011506:Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000099176:Noggin Protein; C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse; C497282:Pax5 protein, mouse; C070835:PAX1 transcription factor