Bmp2 antagonizes sonic hedgehog-mediated proliferation of cerebellar granule neurones through Smad5 signalling.
During development of the cerebellum, sonic hedgehog (Shh) is directly responsible for the proliferation of granule cell precursors in the external germinal layer. We have looked for signals able to regulate a switch from the Shh-mediated proliferative response to one that directs differentiation of granule neurones. Bone morphogenetic proteins (BMPs) are expressed in distinct neuronal populations within the developing cerebellar cortex. Bmp2 and Bmp4 are expressed in the proliferating precursors and subsequently in differentiated granule neurones of the internal granular layer, whereas Bmp7 is expressed by Purkinje neurones. In primary cultures, Bmp2 and Bmp4, but not Bmp7, are able to prevent Shh-induced proliferation, thereby allowing granule neuron differentiation. Furthermore, Bmp2 treatment downregulates components of the Shh pathway in proliferating granule cell precursors. Smad proteins, the only known BMP receptor substrates capable of transducing the signal, are also differentially expressed in the developing cerebellum: Smad1 in the external germinal layer and Smad5 in newly differentiated granule neurones. Among them, only Smad5 is phosphorylated in vivo and in primary cultures treated with Bmp2, and overexpression of Smad5 is sufficient to induce granule cell differentiation in the presence of Shh. We propose a model in which Bmp2-mediated Smad5 signalling suppresses the proliferative response to Shh by downregulation of the pathway, and allows granule cell precursor to enter their differentiation programme.
Rios
Iria
I
Instituto de Biología Molecular de Barcelona (CSIC) Barcelona, C/Josep Samitier 1-5, Barcelona 08028, Spain.
Alvarez-Rodríguez
Rubén
R
Martí
Elisa
E
Pons
Sebastián
S
D000818:Animals; D015153:Blotting, Western; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D002531:Cerebellum / Q000196:embryology / Q000378:metabolism*; D002642:Chick Embryo; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D053823:Hedgehog Proteins; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D009474:Neurons / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051902:Smad5 Protein; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism
C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D053823:Hedgehog Proteins; D010750:Phosphoproteins; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta