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  - Zega, K
AU  - Jovanović, V.M
AU  - Vitić, Z
AU  - Niedzielska, M
AU  - Knaapi, L
AU  - Jukić, Marin
AU  - Partanen, J
AU  - Friedel, R.H
AU  - Lang, R
AU  - Brodski, C
PY  - 2017
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2981
AB  - Hydrocephalus can occur in children alone or in combination with other neurodevelopmental disorders that are often associated with brain overgrowth. Despite the severity of these disorders, the molecular and cellular mechanisms underlying these pathologies and their comorbidity are poorly understood. Here, we studied the consequences of genetically inactivating in mice dual-specificity phosphatase 16 (Dusp16), which is known to negatively regulate mitogen-activated protein kinases (MAPKs) and which has never previously been implicated in brain development and disorders. Mouse mutants lacking a functional Dusp16 gene (Dusp16−/−) developed fully-penetrant congenital obstructive hydrocephalus together with brain overgrowth. The midbrain aqueduct in Dusp16−/− mutants was obstructed during mid-gestation by an expansion of neural progenitors, and during later gestational stages by neurons resulting in a blockage of cerebrospinal fluid (CSF) outflow. In contrast, the roof plate and ependymal cells developed normally. We identified a delayed cell cycle exit of neural progenitors in Dusp16−/− mutants as a cause of progenitor overproliferation during mid-gestation. At later gestational stages, this expanded neural progenitor pool generated an increased number of neurons associated with enlarged brain volume. Taken together, we found that Dusp16 plays a critical role in neurogenesis by balancing neural progenitor cell proliferation and neural differentiation. Moreover our results suggest that a lack of functional Dusp16 could play a central role in the molecular mechanisms linking brain overgrowth and hydrocephalus.
PB  - Frontiers Media S.A.
T2  - Frontiers in Molecular Neuroscience
T1  - Dusp16 deficiency causes congenital obstructive hydrocephalus and brain overgrowth by expansion of the neural progenitor pool
VL  - 10
DO  - 10.3389/fnmol.2017.00372
ER  - 

@article{
author = "Zega, K and Jovanović, V.M and Vitić, Z and Niedzielska, M and Knaapi, L and Jukić, Marin and Partanen, J and Friedel, R.H and Lang, R and Brodski, C",
year = "2017",
abstract = "Hydrocephalus can occur in children alone or in combination with other neurodevelopmental disorders that are often associated with brain overgrowth. Despite the severity of these disorders, the molecular and cellular mechanisms underlying these pathologies and their comorbidity are poorly understood. Here, we studied the consequences of genetically inactivating in mice dual-specificity phosphatase 16 (Dusp16), which is known to negatively regulate mitogen-activated protein kinases (MAPKs) and which has never previously been implicated in brain development and disorders. Mouse mutants lacking a functional Dusp16 gene (Dusp16−/−) developed fully-penetrant congenital obstructive hydrocephalus together with brain overgrowth. The midbrain aqueduct in Dusp16−/− mutants was obstructed during mid-gestation by an expansion of neural progenitors, and during later gestational stages by neurons resulting in a blockage of cerebrospinal fluid (CSF) outflow. In contrast, the roof plate and ependymal cells developed normally. We identified a delayed cell cycle exit of neural progenitors in Dusp16−/− mutants as a cause of progenitor overproliferation during mid-gestation. At later gestational stages, this expanded neural progenitor pool generated an increased number of neurons associated with enlarged brain volume. Taken together, we found that Dusp16 plays a critical role in neurogenesis by balancing neural progenitor cell proliferation and neural differentiation. Moreover our results suggest that a lack of functional Dusp16 could play a central role in the molecular mechanisms linking brain overgrowth and hydrocephalus.",
publisher = "Frontiers Media S.A.",
journal = "Frontiers in Molecular Neuroscience",
title = "Dusp16 deficiency causes congenital obstructive hydrocephalus and brain overgrowth by expansion of the neural progenitor pool",
volume = "10",
doi = "10.3389/fnmol.2017.00372"
}

Zega, K., Jovanović, V.M, Vitić, Z., Niedzielska, M., Knaapi, L., Jukić, M., Partanen, J., Friedel, R.H, Lang, R.,& Brodski, C.. (2017). Dusp16 deficiency causes congenital obstructive hydrocephalus and brain overgrowth by expansion of the neural progenitor pool. in Frontiers in Molecular Neuroscience
Frontiers Media S.A.., 10.
https://doi.org/10.3389/fnmol.2017.00372

Zega K, Jovanović V, Vitić Z, Niedzielska M, Knaapi L, Jukić M, Partanen J, Friedel R, Lang R, Brodski C. Dusp16 deficiency causes congenital obstructive hydrocephalus and brain overgrowth by expansion of the neural progenitor pool. in Frontiers in Molecular Neuroscience. 2017;10.
doi:10.3389/fnmol.2017.00372 .

Zega, K, Jovanović, V.M, Vitić, Z, Niedzielska, M, Knaapi, L, Jukić, Marin, Partanen, J, Friedel, R.H, Lang, R, Brodski, C, "Dusp16 deficiency causes congenital obstructive hydrocephalus and brain overgrowth by expansion of the neural progenitor pool" in Frontiers in Molecular Neuroscience, 10 (2017),
https://doi.org/10.3389/fnmol.2017.00372 . .