TY  - JOUR
AU  - Jovanović, V.M
AU  - Salti, A
AU  - Tilleman, H
AU  - Zega, K
AU  - Jukić, Marin
AU  - Zou, H
AU  - Friedel, R.H
AU  - Prakash, N
AU  - Blaess, S
AU  - Edenhofer, F
AU  - Brodski, C
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3143
AB  - The 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.
PB  - Society for Neuroscience
T2  - Journal of Neuroscience
T1  - BMP/SMAD pathway promotes neurogenesis of midbrain dopaminergic neurons in vivo and in human induced pluripotent and neural stem cells
VL  - 38
IS  - 7
SP  - 1662
EP  - 1676
DO  - 10.1523/JNEUROSCI.1540-17.2018
ER  - 

@article{
author = "Jovanović, V.M and Salti, A and Tilleman, H and Zega, K and Jukić, Marin and Zou, H and Friedel, R.H and Prakash, N and Blaess, S and Edenhofer, F and Brodski, C",
year = "2018",
abstract = "The 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.",
publisher = "Society for Neuroscience",
journal = "Journal of Neuroscience",
title = "BMP/SMAD pathway promotes neurogenesis of midbrain dopaminergic neurons in vivo and in human induced pluripotent and neural stem cells",
volume = "38",
number = "7",
pages = "1662-1676",
doi = "10.1523/JNEUROSCI.1540-17.2018"
}

Jovanović, V.M, Salti, A., Tilleman, H., Zega, K., Jukić, M., Zou, H., Friedel, R.H, Prakash, N., Blaess, S., Edenhofer, F.,& Brodski, C.. (2018). BMP/SMAD pathway promotes neurogenesis of midbrain dopaminergic neurons in vivo and in human induced pluripotent and neural stem cells. in Journal of Neuroscience
Society for Neuroscience., 38(7), 1662-1676.
https://doi.org/10.1523/JNEUROSCI.1540-17.2018

Jovanović V, Salti A, Tilleman H, Zega K, Jukić M, Zou H, Friedel R, Prakash N, Blaess S, Edenhofer F, Brodski C. BMP/SMAD pathway promotes neurogenesis of midbrain dopaminergic neurons in vivo and in human induced pluripotent and neural stem cells. in Journal of Neuroscience. 2018;38(7):1662-1676.
doi:10.1523/JNEUROSCI.1540-17.2018 .

Jovanović, V.M, Salti, A, Tilleman, H, Zega, K, Jukić, Marin, Zou, H, Friedel, R.H, Prakash, N, Blaess, S, Edenhofer, F, Brodski, C, "BMP/SMAD pathway promotes neurogenesis of midbrain dopaminergic neurons in vivo and in human induced pluripotent and neural stem cells" in Journal of Neuroscience, 38, no. 7 (2018):1662-1676,
https://doi.org/10.1523/JNEUROSCI.1540-17.2018 . .