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 . .

TY  - JOUR
AU  - Sherf, O
AU  - Zolotov, L.N
AU  - Liser, K
AU  - Tilleman, H
AU  - Jovanović, V.M
AU  - Zega, K
AU  - Jukić, Marin
AU  - Brodski, C
PY  - 2015
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2520
AB  - Studying the development of mesodiencephalic dopaminergic (mdDA) neurons provides an important basis for better understanding dopamine-associated brain functions and disorders and is critical for establishing cell replacement therapy for Parkinson's disease. The transcription factors Otx2 and Lmx1b play a key role in the development of mdDA neurons. However, little is known about the genes downstream of Otx2 and Lmx1b in the pathways controlling the formation of mdDA neurons in vivo. Here we report on our investigation of Lmx1b as downstream target of Otx2 in the formation of mdDA neurons. Mouse mutants expressing Otx2 under the control of the En1 promoter (En1+/Otx2) showed increased Otx2 expression in the mid-hindbrain region, resulting in upregulation of Lmx1b and expansion of mdDA neurons there. In contrast, Lmx1b-/- mice showed decreased expression of Otx2 and impairments in several aspects of mdDA neuronal formation. To study the functional interaction between Otx2 and Lmx1b, we generated compound mutants in which Otx2 expression was restored in mice lacking Lmx1b (En1+/Otx2;Lmx1b-/-). In these animals Otx2 was not sufficient to rescue any of the aberrations in the formation of mdDA neurons caused by the loss of Lmx1b, but rescued the loss of ocular motor neurons. Gene expression studies in Lmx1b-/- embryos indicated that in these mutants Wnt1, En1 and Fgf8 expression are induced but subsequently lost in the mdDA precursor domain and the mid-hindbrain organizer in a specific, spatio-temporal manner. In summary, we demonstrate that Otx2 critically depends on Lmx1b for the formation of mdDA neurons, but not for the generation of ocular motor neurons. Moreover, our data suggest that Lmx1b precisely maintains the expression pattern of Wnt1, Fgf8 and En1, which are essential for mid-hindbrain organizer function and the formation of mdDA neurons.
PB  - Public Library of Science
T2  - PLoS One
T1  - Otx2 requires Lmx1b to control the development of mesodiencephalic dopaminergic neurons
VL  - 10
IS  - 10
DO  - 10.1371/journal.pone.0139697
ER  - 

@article{
author = "Sherf, O and Zolotov, L.N and Liser, K and Tilleman, H and Jovanović, V.M and Zega, K and Jukić, Marin and Brodski, C",
year = "2015",
abstract = "Studying the development of mesodiencephalic dopaminergic (mdDA) neurons provides an important basis for better understanding dopamine-associated brain functions and disorders and is critical for establishing cell replacement therapy for Parkinson's disease. The transcription factors Otx2 and Lmx1b play a key role in the development of mdDA neurons. However, little is known about the genes downstream of Otx2 and Lmx1b in the pathways controlling the formation of mdDA neurons in vivo. Here we report on our investigation of Lmx1b as downstream target of Otx2 in the formation of mdDA neurons. Mouse mutants expressing Otx2 under the control of the En1 promoter (En1+/Otx2) showed increased Otx2 expression in the mid-hindbrain region, resulting in upregulation of Lmx1b and expansion of mdDA neurons there. In contrast, Lmx1b-/- mice showed decreased expression of Otx2 and impairments in several aspects of mdDA neuronal formation. To study the functional interaction between Otx2 and Lmx1b, we generated compound mutants in which Otx2 expression was restored in mice lacking Lmx1b (En1+/Otx2;Lmx1b-/-). In these animals Otx2 was not sufficient to rescue any of the aberrations in the formation of mdDA neurons caused by the loss of Lmx1b, but rescued the loss of ocular motor neurons. Gene expression studies in Lmx1b-/- embryos indicated that in these mutants Wnt1, En1 and Fgf8 expression are induced but subsequently lost in the mdDA precursor domain and the mid-hindbrain organizer in a specific, spatio-temporal manner. In summary, we demonstrate that Otx2 critically depends on Lmx1b for the formation of mdDA neurons, but not for the generation of ocular motor neurons. Moreover, our data suggest that Lmx1b precisely maintains the expression pattern of Wnt1, Fgf8 and En1, which are essential for mid-hindbrain organizer function and the formation of mdDA neurons.",
publisher = "Public Library of Science",
journal = "PLoS One",
title = "Otx2 requires Lmx1b to control the development of mesodiencephalic dopaminergic neurons",
volume = "10",
number = "10",
doi = "10.1371/journal.pone.0139697"
}

Sherf, O., Zolotov, L.N, Liser, K., Tilleman, H., Jovanović, V.M, Zega, K., Jukić, M.,& Brodski, C.. (2015). Otx2 requires Lmx1b to control the development of mesodiencephalic dopaminergic neurons. in PLoS One
Public Library of Science., 10(10).
https://doi.org/10.1371/journal.pone.0139697

Sherf O, Zolotov L, Liser K, Tilleman H, Jovanović V, Zega K, Jukić M, Brodski C. Otx2 requires Lmx1b to control the development of mesodiencephalic dopaminergic neurons. in PLoS One. 2015;10(10).
doi:10.1371/journal.pone.0139697 .

Sherf, O, Zolotov, L.N, Liser, K, Tilleman, H, Jovanović, V.M, Zega, K, Jukić, Marin, Brodski, C, "Otx2 requires Lmx1b to control the development of mesodiencephalic dopaminergic neurons" in PLoS One, 10, no. 10 (2015),
https://doi.org/10.1371/journal.pone.0139697 . .