title: Gremlin is the BMP antagonist required for maintenance of Shh and Fgf signals during limb patterning.
abstract: During limb outgrowth, signaling by bone morphogenetic proteins (BMPs) must be moderated to maintain the signaling loop between the zone of polarizing activity (ZPA) and the apical ectodermal ridge (AER). Gremlin, an extracellular Bmp antagonist, has been proposed to fulfill this function and therefore be important in limb patterning. We tested this model directly by mutating the mouse gene encoding gremlin (Cktsf1b1, herein called gremlin). In the mutant limb, the feedback loop between the ZPA and the AER is interrupted, resulting in abnormal skeletal pattern. We also show that the gremlin mutation is allelic to the limb deformity mutation (ld). Although Bmps and their antagonists have multiple roles in limb development, these experiments show that gremlin is the principal BMP antagonist required for early limb outgrowth and patterning.
authors.affiliation: Department of Molecular and Cell Biology, University of California-Berkeley, 401 Barker Hall, Berkeley, California 94720, USA.
authors.forename: Mustafa K
authors.initials: MK
authors.lastname: Khokha
authors.forename: David
authors.initials: D
authors.lastname: Hsu
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Brunet
authors.forename: Marc S
authors.initials: MS
authors.lastname: Dionne
authors.forename: Richard M
authors.initials: RM
authors.lastname: Harland
mesh_terms: D000818:Animals; D019521:Body Patterning; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D001842:Bone and Bones / Q000378:metabolism; D016207:Cytokines; D004627:Embryonic Induction; D005260:Female; D005326:Fetal Proteins / Q000378:metabolism; D051519:Fibroblast Growth Factor 4; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005552:Forelimb / Q000196:embryology*; D000080865:Formins; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D006614:Hindlimb / Q000196:embryology*; D036341:Intercellular Signaling Peptides and Proteins; D018878:Limb Buds / Q000166:cytology / Q000196:embryology; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D011506:Proteins / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D016207:Cytokines; D005326:Fetal Proteins; D051519:Fibroblast Growth Factor 4; D005346:Fibroblast Growth Factors; D000080865:Formins; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; C113178:Grem1 protein, mouse; C496446:Fgf4 protein, mouse; C465570:Shh protein, mouse