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dc.creatorJovanović, V.M
dc.creatorSalti, A
dc.creatorTilleman, H
dc.creatorZega, K
dc.creatorJukić, Marin
dc.creatorZou, H
dc.creatorFriedel, R.H
dc.creatorPrakash, N
dc.creatorBlaess, S
dc.creatorEdenhofer, F
dc.creatorBrodski, C
dc.date.accessioned2019-09-02T12:05:54Z
dc.date.available2019-09-02T12:05:54Z
dc.date.issued2018
dc.identifier.issn0270-6474
dc.identifier.urihttp://farfar.pharmacy.bg.ac.rs/handle/123456789/3143
dc.description.abstractThe embryonic formation of midbrain dopaminergic (mDA) neurons in vivo provides critical guidelines for the in vitro differentiation of mDA neurons from stem cells, which are currently being developed for Parkinson’s disease cell replacement therapy. Bone morphogenetic protein (BMP)/SMAD inhibition is routinely used during early steps of stem cell differentiation protocols, including for the generation of mDA neurons. However, the function of the BMP/SMAD pathway for in vivo specification of mammalian mDA neurons is virtually unknown. Here, we report that BMP5/7-deficient mice (Bmp5 -/- ; Bmp7 -/- ) lackmDAneurons due to reduced neurogenesis in the mDA progenitor domain. As molecular mechanisms accounting for these alterations in Bmp5 -/- ; Bmp7 -/- mutants, we have identified expression changes of the BMP/SMAD target genes MSX1/2 (msh homeobox 1/2) and SHH (sonic hedgehog). Conditionally inactivatingSMAD1in neural stem cells of mice in vivo (Smad1 Nes ) hampered the differentiation of progenitor cells intomDAneurons by preventing cell cycle exit, especially of TH + SOX6 + (tyrosine hydroxylase, SRY-box 6) and TH + GIRK2 + (potassium voltage-gated channel subfamily-J member-6) substantia nigra neurons. BMP5/7 robustly increased the in vitro differentiation of human induced pluripotent stem cells and induced neural stem cells to mDA neurons by up to threefold. In conclusion, we have identified BMP/SMAD signaling as a novel critical pathway orchestrating essential steps of mammalian mDA neurogenesis in vivo that balances progenitor proliferation and differentiation. Moreover, we demonstrate the potential of BMPs to improve the generation of stem-cell-derived mDA neurons in vitro, highlighting the importance of sequential BMP/SMAD inhibition and activation in this process.en
dc.publisherSociety for Neuroscience
dc.relationIsraeli Science Foundation (Grant1391/11toC.B.)
dc.relationDeutsche Forschungsge-meinschaft (DFG 79/4-1 to F.E.; DFG BL 767 / 2-1 and DFG BL 767 / 3-1 to SB)
dc.relationBavarian Research Network on Induced Pluripotent Stem Cells (For IPS to F.E.)
dc.rightsopenAccess
dc.sourceJournal of Neuroscience
dc.subjectEmbryonic developmenten
dc.subjectIPSCen
dc.subjectMidbrain dopaminergic neuronsen
dc.subjectNeurogenesisen
dc.subjectNeuronal differentiationen
dc.subjectStem cellsen
dc.titleBMP/SMAD pathway promotes neurogenesis of midbrain dopaminergic neurons in vivo and in human induced pluripotent and neural stem cellsen
dc.typearticle
dc.rights.licenseARR
dcterms.abstractТиллеман, Х; Зега, К; Фриедел, Р.Х; Бродски, Ц; Јукић, Марин; Салти, A; Зоу, Х; Пракасх, Н; Блаесс, С; Еденхофер, Ф; Јовановић, В.М;
dc.citation.volume38
dc.citation.issue7
dc.citation.spage1662
dc.citation.epage1676
dc.citation.other38(7): 1662-1676
dc.citation.rankM21
dc.identifier.wos000424987700007
dc.identifier.doi10.1523/JNEUROSCI.1540-17.2018
dc.identifier.scopus2-s2.0-85042105924
dc.identifier.fulltexthttp://farfar.pharmacy.bg.ac.rs//bitstream/id/1727/3141.pdf
dc.identifier.rcubconv_4615
dc.type.versionpublishedVersion


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