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 . .

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 . .

TY  - JOUR
AU  - Jukić, Marin
AU  - Carrillo-Roa, T
AU  - Bar, M
AU  - Becker, G
AU  - Jovanović, V.M
AU  - Zega, K
AU  - Binder, E.B
AU  - Brodski, C
PY  - 2015
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2488
AB  - Subtle mood fluctuations are normal emotional experiences, whereas drastic mood swings can be a manifestation of bipolar disorder (BPD). Despite their importance for normal and pathological behavior, the mechanisms underlying endogenous mood instability are largely unknown. During embryogenesis, the transcription factor Otx2 orchestrates the genetic networks directing the specification of dopaminergic (DA) and serotonergic (5-HT) neurons. Here we behaviorally phenotyped mouse mutants overexpressing Otx2 in the hindbrain, resulting in an increased number of DA neurons and a decreased number of 5-HT neurons in both developing and mature animals. Over the course of 1 month, control animals exhibited stable locomotor activity in their home cages, whereas mutants showed extended periods of elevated or decreased activity relative to their individual average. Additional behavioral paradigms, testing for manic-and depressive-like behavior, demonstrated that mutants showed an increase in intra-individual fluctuations in locomotor activity, habituation, risk-taking behavioral parameters, social interaction, and hedonic-like behavior. Olanzapine, lithium, and carbamazepine ameliorated the behavioral alterations of the mutants, as did the mixed serotonin receptor agonist quipazine and the specific 5-HT 2C receptor agonist CP-809101. Testing the relevance of the genetic networks specifying monoaminergic neurons for BPD in humans, we applied an interval-based enrichment analysis tool for genome-wide association studies. We observed that the genes specifying DA and 5-HT neurons exhibit a significant level of aggregated association with BPD but not with schizophrenia or major depressive disorder. The results of our translational study suggest that aberrant development of monoaminergic neurons leads to mood fluctuations and may be associated with BPD.
PB  - Nature Publishing Group
T2  - Neuropsychopharmacology
T1  - Abnormal development of monoaminergic neurons is implicated in mood fluctuations and bipolar disorder
VL  - 40
IS  - 4
SP  - 839
EP  - 848
DO  - 10.1038/npp.2014.244
ER  - 

@article{
author = "Jukić, Marin and Carrillo-Roa, T and Bar, M and Becker, G and Jovanović, V.M and Zega, K and Binder, E.B and Brodski, C",
year = "2015",
abstract = "Subtle mood fluctuations are normal emotional experiences, whereas drastic mood swings can be a manifestation of bipolar disorder (BPD). Despite their importance for normal and pathological behavior, the mechanisms underlying endogenous mood instability are largely unknown. During embryogenesis, the transcription factor Otx2 orchestrates the genetic networks directing the specification of dopaminergic (DA) and serotonergic (5-HT) neurons. Here we behaviorally phenotyped mouse mutants overexpressing Otx2 in the hindbrain, resulting in an increased number of DA neurons and a decreased number of 5-HT neurons in both developing and mature animals. Over the course of 1 month, control animals exhibited stable locomotor activity in their home cages, whereas mutants showed extended periods of elevated or decreased activity relative to their individual average. Additional behavioral paradigms, testing for manic-and depressive-like behavior, demonstrated that mutants showed an increase in intra-individual fluctuations in locomotor activity, habituation, risk-taking behavioral parameters, social interaction, and hedonic-like behavior. Olanzapine, lithium, and carbamazepine ameliorated the behavioral alterations of the mutants, as did the mixed serotonin receptor agonist quipazine and the specific 5-HT 2C receptor agonist CP-809101. Testing the relevance of the genetic networks specifying monoaminergic neurons for BPD in humans, we applied an interval-based enrichment analysis tool for genome-wide association studies. We observed that the genes specifying DA and 5-HT neurons exhibit a significant level of aggregated association with BPD but not with schizophrenia or major depressive disorder. The results of our translational study suggest that aberrant development of monoaminergic neurons leads to mood fluctuations and may be associated with BPD.",
publisher = "Nature Publishing Group",
journal = "Neuropsychopharmacology",
title = "Abnormal development of monoaminergic neurons is implicated in mood fluctuations and bipolar disorder",
volume = "40",
number = "4",
pages = "839-848",
doi = "10.1038/npp.2014.244"
}

Jukić, M., Carrillo-Roa, T., Bar, M., Becker, G., Jovanović, V.M, Zega, K., Binder, E.B,& Brodski, C.. (2015). Abnormal development of monoaminergic neurons is implicated in mood fluctuations and bipolar disorder. in Neuropsychopharmacology
Nature Publishing Group., 40(4), 839-848.
https://doi.org/10.1038/npp.2014.244

Jukić M, Carrillo-Roa T, Bar M, Becker G, Jovanović V, Zega K, Binder E, Brodski C. Abnormal development of monoaminergic neurons is implicated in mood fluctuations and bipolar disorder. in Neuropsychopharmacology. 2015;40(4):839-848.
doi:10.1038/npp.2014.244 .

Jukić, Marin, Carrillo-Roa, T, Bar, M, Becker, G, Jovanović, V.M, Zega, K, Binder, E.B, Brodski, C, "Abnormal development of monoaminergic neurons is implicated in mood fluctuations and bipolar disorder" in Neuropsychopharmacology, 40, no. 4 (2015):839-848,
https://doi.org/10.1038/npp.2014.244 . .