Retroviral manipulation of the expression of bone morphogenetic protein receptor Ia by SVZa progenitor cells leads to changes in their p19(INK4d) expression but not in their neuronal commitment.
Bone morphogenetic proteins (BMPs), a group of cytokines in the TGF-beta superfamily, have complex regulatory roles in the control of neural proliferation and cell fate decision. In this study, we analyzed the potential role(s) of BMP signaling on the regulation of the proliferation and differentiation of the unique progenitor cells of the neonatal anterior subventricular zone (SVZa). Unlike other progenitor cells of the brain, SVZa progenitor cells have the capacity to divide even though they express a neuronal phenotype. In order to augment or inhibit endogenous BMP signaling, we injected into the neonatal rat SVZa replication-deficient retroviruses encoding for either the wild-type BMP receptor subtype Ia (wt-BMPR-Ia) or a mutated dominant-negative version of BMPR-Ia (dn-BMPR-Ia) in conjunction with a reporter gene, human alkaline phosphatase (AP) and perfused the pups 1, 4 and 7 days post injection. We analyzed whether changing the expression of BMPR-Ia has an effect on the spatial-temporal expression pattern of the cyclin dependent kinase inhibitor, p19(INK4d), or on the phenotype of SVZa derived cells. The results of our study confirmed and extended our previous findings that in control (non injected) animals, the rostral migratory stream (RMS), traversed by the SVZa-derived cells en route to the olfactory bulb, exhibits an anterior(high)-posterior(low) gradient of p19(INK4d) expression; p19(INK4d) expression is essentially absent in the SVZa and highest in the subependymal zone in the middle of the olfactory bulb. However, SVZa progenitor cells encoding the wt-BMPR-Ia gene express p19(INK4d) within the SVZa, suggesting that the BMPs induce SVZa cells to ectopically undergo cell cycle exit within the SVZa. Furthermore, unlike striatal SVZ progenitor cells, which acquire an astrocytic phenotype when exposed to BMPs, SVZa progenitor cells retain their neuronal commitment under augmented BMP signaling.
Department of Cell Biology, Emory University School of Medicine, 1648 Pierce Drive, Atlanta, GA 30322, USA.
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V
Coskun
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Venkatraman
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H
Yang
M S
MS
Rao
M B
MB
Luskin
D000469:Alkaline Phosphatase / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D052005:Bone Morphogenetic Protein Receptors, Type I; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D019070:Cell Lineage; D002465:Cell Movement; D002552:Cerebral Ventricles / Q000196:embryology; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050764:Cyclin-Dependent Kinase Inhibitor p19; D003673:Defective Viruses / Q000235:genetics; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D009024:Morphogenesis; D009475:Neurons, Afferent / Q000166:cytology*; D009830:Olfactory Bulb / Q000166:cytology* / Q000196:embryology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017978:Receptors, Growth Factor / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D012190:Retroviridae / Q000235:genetics; D014162:Transfection
D019485:Bone Morphogenetic Proteins; C493974:CDKN2D protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050764:Cyclin-Dependent Kinase Inhibitor p19; D017978:Receptors, Growth Factor; D011993:Recombinant Fusion Proteins; D017346:Protein Serine-Threonine Kinases; C498211:BMPR1A protein, human; C498213:Bmpr1a protein, rat; C498216:Bmpr1b protein, rat; D052005:Bone Morphogenetic Protein Receptors, Type I; D000469:Alkaline Phosphatase