Shh establishes an Nkx3.2/Sox9 autoregulatory loop that is maintained by BMP signals to induce somitic chondrogenesis.
Prior work has established that transient Shh signals from the notochord and floor plate confer a competence in somitic tissue for subsequent BMP signals to induce chondrogenesis. We have therefore proposed that Shh induces a factor(s) that renders somitic cells competent to chondrify in response to subsequent BMP signals. Recently, we have shown that forced expression of Nkx3.2, a transcriptional repressor induced by Shh, is able to confer chondrogenic competence in somites. In this work, we show that administration of Shh or forced Nkx3.2 expression induces the expression of the transcription factor Sox9 in the somitic tissue. Forced expression of Sox9 can, in turn, induce robust chondrogenesis in somitic mesoderm, provided that BMP signals are present. We have found that in the presence of BMP signals, Sox9 and Nkx3.2 induce each other's expression. Thus, Nkx3.2 may promote axial chondrogenesis by derepressing the expression of Sox9 in somitic mesoderm. Furthermore, forced expression of either Sox9 or Nkx3.2 not only activates expression of cartilage-specific genes in somitic mesoderm, but also promotes the proliferation and survival of the induced chondrocytes in the presence of BMP signals. However, unlike Nkx3.2, Sox9 is able to induce de novo cartilage formation in non-cartilage-forming tissues. Our findings suggest that Shh and BMP signals work in sequence to establish a positive regulatory loop between Sox9 and Nkx3.2, and that Sox9 can subsequently initiate the chondrocyte differentiation program in a variety of cellular environments.
Zeng
Li
L
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Kempf
Hervé
H
Murtaugh
L Charles
LC
Sato
Mie Elissa
ME
Lassar
Andrew B
AB
D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics; D017209:Apoptosis; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D016466:CHO Cells; D002352:Carrier Proteins; D002356:Cartilage / Q000196:embryology*; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage; D002642:Chick Embryo; D006224:Cricetinae; D003412:Cricetulus; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005246:Feedback; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D053823:Hedgehog Proteins; D006609:High Mobility Group Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008648:Mesoderm / Q000378:metabolism*; D009924:Organ Culture Techniques; D011506:Proteins / Q000502:physiology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D055758:SOX9 Transcription Factor; D019170:Somites / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*; D016212:Transforming Growth Factor beta; D000099176:Noggin Protein
D000943:Antigens, Differentiation; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D017077:Culture Media, Conditioned; D053823:Hedgehog Proteins; D006609:High Mobility Group Proteins; D018398:Homeodomain Proteins; D011506:Proteins; D012097:Repressor Proteins; D055758:SOX9 Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000099176:Noggin Protein