The Experts below are selected from a list of 162 Experts worldwide ranked by ideXlab platform
Antonio Simeone - One of the best experts on this subject based on the ideXlab platform.
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Otx2 expression is restricted to dopaminergic neurons of the ventral tegmental area in the adult brain.
The International Journal of Developmental Biology, 2020Co-Authors: Michela Salvio, Dario Acampora, Luca Giovanni Giovannantonio, Daniela Omodei, Antonio SimeoneAbstract:Mesencephalic-diencephalic dopaminergic (mdDA) neurons control motor, sensorimotor and motivated behaviour and their degeneration or abnormal functioning is associated with important pathologies, such as Parkinson’s disease and psychiatric disorders. Despite great efforts, the molecular basis and the genetic Factors differentially controlling identity, survival and vulnerability to neurodegeneration of mdDA neurons of the substantia nigra (SN) and ventral tegmental area (VTA) are poorly understood. We have previously shown that the Transcription Factor Otx2 is required for identity, fate and proliferation of mesencephalic DA (mesDA) progenitors. By using mouse models and immunohistochemistry, we have investigated whether Otx2 is expressed also in post-mitotic mdDA neurons. Our data reveal that Otx2 is expressed in post-mitotic mesDA neurons during mid-late gestation and in the adult brain. Remarkably, Otx2 expression is sharply excluded from mdDA neurons of the SN and is restricted to a relevant fraction of VTA neurons. Otx2+-TH+ neurons are concentrated to the ventral part of the VTA. Combined expression with other regionalized VTA markers shows that Otx2+-TH+ neurons are prevalently Girk2- and Calb+ and among these, those located in the medial and ventralmost portion of the VTA are also Ahd2+. These findings indicate that Otx2 represents the first Transcription Factor with a proven role in mdDA neurogenesis whose expression discriminates between SN and a relevant proportion of VTA neurons. This supports the possibility that Otx2 may act as a post-mitotic selector controlling functional features (e.g. identity and/or survival) of a relevant fraction of VTA neurons in the adult.
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Otx2 restricts entry to the mouse germline
Nature, 2018Co-Authors: Jingchao Zhang, Dario Acampora, Antonio Simeone, Man Zhang, Matúš Vojtek, Detian Yuan, Ian ChambersAbstract:The successful segregation of germ cells from somatic lineages is vital for sexual reproduction and species survival. In the mouse, primordial germ cells (PGCs), precursors of all germ cells, are induced from the post-implantation epiblast1. Induction requires BMP4 signalling to prospective PGCs2 and the intrinsic action of PGC Transcription Factors3–6. However, the molecular mechanisms that connect BMP4 to induction of the PGC Transcription Factors that are responsible for segregating PGCs from somatic lineages are unknown. Here we show that the Transcription Factor Otx2 is a key regulator of these processes. Downregulation of Otx2 precedes the initiation of the PGC programme both in vitro and in vivo. Deletion of Otx2 in vitro markedly increases the efficiency of PGC-like cell differentiation and prolongs the period of PGC competence. In the absence of Otx2 activity, differentiation of PGC-like cells becomes independent of the otherwise essential cytokine signals, with germline entry initiating even in the absence of the PGC Transcription Factor BLIMP1. Deletion of Otx2 in vivo increases PGC numbers. These data demonstrate that Otx2 functions repressively upstream of PGC Transcription Factors, acting as a roadblock to limit entry of epiblast cells to the germline to a small window in space and time, thereby ensuring correct numerical segregation of germline cells from the soma.
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Otx2 cell autonomously determines dorsal mesencephalon versus cerebellum fate independently of isthmic organizing activity
Development, 2014Co-Authors: Luca Giovanni Giovannantonio, Dario Acampora, Michela Salvio, Daniela Omodei, Nilima Prakash, Wolfgang Wurst, Alessandra Pierani, Antonio SimeoneAbstract:During embryonic development, the rostral neuroectoderm is regionalized into broad areas that are subsequently subdivided into progenitor compartments with specialized identity and fate. These events are controlled by signals emitted by organizing centers and interpreted by target progenitors, which activate superimposing waves of intrinsic Factors restricting their identity and fate. The Transcription Factor Otx2 plays a crucial role in mesencephalic development by positioning the midbrain-hindbrain boundary (MHB) and its organizing activity. Here, we investigated whether Otx2 is cell-autonomously required to control identity and fate of dorsal mesencephalic progenitors. With this aim, we have inactivated Otx2 in the Pax7 + dorsal mesencephalic domain, previously named m1, without affecting MHB integrity. We found that the Pax7 + m1 domain can be further subdivided into a dorsal Zic1 + m1a and a ventral Zic1 - m1b sub-domain. Loss of Otx2 in the m1a (Pax7 + Zic1 + ) sub-domain impairs the identity and fate of progenitors, which undergo a full switch into a coordinated cerebellum differentiation program. By contrast, in the m1b sub-domain (Pax7 + Zic1 - ) Otx2 is prevalently required for post-mitotic transition of mesencephalic GABAergic precursors. Moreover, genetic cell fate, BrdU cell labeling and Otx2 conditional inactivation experiments indicate that in Otx2 mutants all ectopic cerebellar cell types, including external granule cell layer (EGL) precursors, originate from the m1a progenitor sub-domain and that reprogramming of mesencephalic precursors into EGL or cerebellar GABAergic progenitors depends on temporal sensitivity to Otx2 ablation. Together, these findings indicate that Otx2 intrinsically controls different aspects of dorsal mesencephalic neurogenesis. In this context, Otx2 is cell-autonomously required in the m1a sub-domain to suppress cerebellar fate and promote mesencephalic differentiation independently of the MHB organizing activity.
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Increased dopaminergic innervation in the brain of conditional mutant mice overexpressing Otx2: effects on locomotor behavior and seizure susceptibility.
Neuroscience, 2013Co-Authors: Prem Prakash Tripathi, Dario Acampora, Antonio Simeone, Wolfgang Wurst, L. G. Di Giovannantonio, E. Sanguinetti, Manuela Allegra, Matteo Caleo, Yuri BozziAbstract:The homeobox-containing Transcription Factor Otx2 controls the identity, fate and proliferation of mesencephalic dopaminergic (mesDA) neurons. Transgenic mice, in which Otx2 was conditionally overexpressed by a Cre recombinase expressed under the Transcriptional control of the Engrailed1 gene (En1Cre/+; tOtx2ov/+), show an increased number of mesDA neurons during development. In adult mice, Otx2 is expressed in a subset of neurons in the ventral tegmental area (VTA) and its overexpression renders mesDA more resistant to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-HCl (MPTP) neurotoxin. Here we further investigated the neurological consequences of the increased number of mesDA neurons in En1Cre/+; tOtx2ov/+ adult mice. Immunohistochemistry for the active, glycosylated form of the dopamine transporter (glyco-Dat) showed that En1Cre/+; tOtx2ov/+ adult mice display an increased density of mesocortical DAergic fibers, as compared to control animals. Increased glyco-Dat staining was accompanied by a marked hypolocomotion in En1Cre/+; tOtx2ov/+ mice, as detected in the open field test. Since conditional knockout mice lacking Otx2 in mesDA precursors (En1Cre/+; Otx2floxv/flox mice) show a marked resistance to kainic acid (KA)-induced seizures, we investigated the behavioral response to KA in En1Cre/+; tOtx2ov/+ and control mice. No difference was observed between mutant and control mice, but En1Cre/+; tOtx2ov/+ mice showed a markedly different c-fos mRNA induction profile in the cerebral cortex and hippocampus after KA seizures, as compared to controls. Accordingly, an increased density of parvalbumin (PV)-positive inhibitory interneurons was detected in the deep layers of the frontal cortex of naive En1Cre/+; tOtx2ov/+ mice, as compared to controls. These data indicate that Otx2 overexpression results in increased DAergic innervation and PV cell density in the fronto-parietal cortex, with important consequences on spontaneous locomotor activity and seizure-induced gene expression. Our results strengthen the notion that Otx2 mutant mouse models are a powerful genetic tool to unravel the molecular and behavioral consequences of altered development of the DAergic system.
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the Transcription Factor Otx2 regulates choroid plexus development and function
Development, 2013Co-Authors: Pia A Johansson, Martin Irmler, Dario Acampora, Johannes Beckers, Antonio Simeone, Magdalena GotzAbstract:The choroid plexuses (ChPs) are the main regulators of cerebrospinal fluid (CSF) composition and thereby also control the composition of a principal source of signaling molecules that is in direct contact with neural stem cells in the developing brain. The regulators of ChP development mediating the acquisition of a fate that differs from the neighboring neuroepithelial cells are poorly understood. Here, we demonstrate in mice a crucial role for the Transcription Factor Otx2 in the development and maintenance of ChP cells. Deletion of Otx2 by the Otx2-CreERT2 driver line at E9 resulted in a lack of all ChPs, whereas deletion by the Gdf7-Cre driver line affected predominately the hindbrain ChP, which was reduced in size, primarily owing to an increase in apoptosis upon Otx2 deletion. Strikingly, Otx2 was still required for the maintenance of hindbrain ChP cells at later stages when Otx2 deletion was induced at E15, demonstrating a central role of Otx2 in ChP development and maintenance. Moreover, the predominant defects in the hindbrain ChP mediated by Gdf7-Cre deletion of Otx2 revealed its key role in regulating early CSF composition, which was altered in protein content, including the levels of Wnt4 and the Wnt modulator Tgm2. Accordingly, proliferation and Wnt signaling levels were increased in the distant cerebral cortex, suggesting a role of the hindbrain ChP in regulating CSF composition, including key signaling molecules. Thus, Otx2 acts as a master regulator of ChP development, thereby influencing one of the principal sources of signaling in the developing brain, the CSF.
Dario Acampora - One of the best experts on this subject based on the ideXlab platform.
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Otx2 expression is restricted to dopaminergic neurons of the ventral tegmental area in the adult brain.
The International Journal of Developmental Biology, 2020Co-Authors: Michela Salvio, Dario Acampora, Luca Giovanni Giovannantonio, Daniela Omodei, Antonio SimeoneAbstract:Mesencephalic-diencephalic dopaminergic (mdDA) neurons control motor, sensorimotor and motivated behaviour and their degeneration or abnormal functioning is associated with important pathologies, such as Parkinson’s disease and psychiatric disorders. Despite great efforts, the molecular basis and the genetic Factors differentially controlling identity, survival and vulnerability to neurodegeneration of mdDA neurons of the substantia nigra (SN) and ventral tegmental area (VTA) are poorly understood. We have previously shown that the Transcription Factor Otx2 is required for identity, fate and proliferation of mesencephalic DA (mesDA) progenitors. By using mouse models and immunohistochemistry, we have investigated whether Otx2 is expressed also in post-mitotic mdDA neurons. Our data reveal that Otx2 is expressed in post-mitotic mesDA neurons during mid-late gestation and in the adult brain. Remarkably, Otx2 expression is sharply excluded from mdDA neurons of the SN and is restricted to a relevant fraction of VTA neurons. Otx2+-TH+ neurons are concentrated to the ventral part of the VTA. Combined expression with other regionalized VTA markers shows that Otx2+-TH+ neurons are prevalently Girk2- and Calb+ and among these, those located in the medial and ventralmost portion of the VTA are also Ahd2+. These findings indicate that Otx2 represents the first Transcription Factor with a proven role in mdDA neurogenesis whose expression discriminates between SN and a relevant proportion of VTA neurons. This supports the possibility that Otx2 may act as a post-mitotic selector controlling functional features (e.g. identity and/or survival) of a relevant fraction of VTA neurons in the adult.
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Otx2 restricts entry to the mouse germline
Nature, 2018Co-Authors: Jingchao Zhang, Dario Acampora, Antonio Simeone, Man Zhang, Matúš Vojtek, Detian Yuan, Ian ChambersAbstract:The successful segregation of germ cells from somatic lineages is vital for sexual reproduction and species survival. In the mouse, primordial germ cells (PGCs), precursors of all germ cells, are induced from the post-implantation epiblast1. Induction requires BMP4 signalling to prospective PGCs2 and the intrinsic action of PGC Transcription Factors3–6. However, the molecular mechanisms that connect BMP4 to induction of the PGC Transcription Factors that are responsible for segregating PGCs from somatic lineages are unknown. Here we show that the Transcription Factor Otx2 is a key regulator of these processes. Downregulation of Otx2 precedes the initiation of the PGC programme both in vitro and in vivo. Deletion of Otx2 in vitro markedly increases the efficiency of PGC-like cell differentiation and prolongs the period of PGC competence. In the absence of Otx2 activity, differentiation of PGC-like cells becomes independent of the otherwise essential cytokine signals, with germline entry initiating even in the absence of the PGC Transcription Factor BLIMP1. Deletion of Otx2 in vivo increases PGC numbers. These data demonstrate that Otx2 functions repressively upstream of PGC Transcription Factors, acting as a roadblock to limit entry of epiblast cells to the germline to a small window in space and time, thereby ensuring correct numerical segregation of germline cells from the soma.
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Otx2 cell autonomously determines dorsal mesencephalon versus cerebellum fate independently of isthmic organizing activity
Development, 2014Co-Authors: Luca Giovanni Giovannantonio, Dario Acampora, Michela Salvio, Daniela Omodei, Nilima Prakash, Wolfgang Wurst, Alessandra Pierani, Antonio SimeoneAbstract:During embryonic development, the rostral neuroectoderm is regionalized into broad areas that are subsequently subdivided into progenitor compartments with specialized identity and fate. These events are controlled by signals emitted by organizing centers and interpreted by target progenitors, which activate superimposing waves of intrinsic Factors restricting their identity and fate. The Transcription Factor Otx2 plays a crucial role in mesencephalic development by positioning the midbrain-hindbrain boundary (MHB) and its organizing activity. Here, we investigated whether Otx2 is cell-autonomously required to control identity and fate of dorsal mesencephalic progenitors. With this aim, we have inactivated Otx2 in the Pax7 + dorsal mesencephalic domain, previously named m1, without affecting MHB integrity. We found that the Pax7 + m1 domain can be further subdivided into a dorsal Zic1 + m1a and a ventral Zic1 - m1b sub-domain. Loss of Otx2 in the m1a (Pax7 + Zic1 + ) sub-domain impairs the identity and fate of progenitors, which undergo a full switch into a coordinated cerebellum differentiation program. By contrast, in the m1b sub-domain (Pax7 + Zic1 - ) Otx2 is prevalently required for post-mitotic transition of mesencephalic GABAergic precursors. Moreover, genetic cell fate, BrdU cell labeling and Otx2 conditional inactivation experiments indicate that in Otx2 mutants all ectopic cerebellar cell types, including external granule cell layer (EGL) precursors, originate from the m1a progenitor sub-domain and that reprogramming of mesencephalic precursors into EGL or cerebellar GABAergic progenitors depends on temporal sensitivity to Otx2 ablation. Together, these findings indicate that Otx2 intrinsically controls different aspects of dorsal mesencephalic neurogenesis. In this context, Otx2 is cell-autonomously required in the m1a sub-domain to suppress cerebellar fate and promote mesencephalic differentiation independently of the MHB organizing activity.
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Increased dopaminergic innervation in the brain of conditional mutant mice overexpressing Otx2: effects on locomotor behavior and seizure susceptibility.
Neuroscience, 2013Co-Authors: Prem Prakash Tripathi, Dario Acampora, Antonio Simeone, Wolfgang Wurst, L. G. Di Giovannantonio, E. Sanguinetti, Manuela Allegra, Matteo Caleo, Yuri BozziAbstract:The homeobox-containing Transcription Factor Otx2 controls the identity, fate and proliferation of mesencephalic dopaminergic (mesDA) neurons. Transgenic mice, in which Otx2 was conditionally overexpressed by a Cre recombinase expressed under the Transcriptional control of the Engrailed1 gene (En1Cre/+; tOtx2ov/+), show an increased number of mesDA neurons during development. In adult mice, Otx2 is expressed in a subset of neurons in the ventral tegmental area (VTA) and its overexpression renders mesDA more resistant to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-HCl (MPTP) neurotoxin. Here we further investigated the neurological consequences of the increased number of mesDA neurons in En1Cre/+; tOtx2ov/+ adult mice. Immunohistochemistry for the active, glycosylated form of the dopamine transporter (glyco-Dat) showed that En1Cre/+; tOtx2ov/+ adult mice display an increased density of mesocortical DAergic fibers, as compared to control animals. Increased glyco-Dat staining was accompanied by a marked hypolocomotion in En1Cre/+; tOtx2ov/+ mice, as detected in the open field test. Since conditional knockout mice lacking Otx2 in mesDA precursors (En1Cre/+; Otx2floxv/flox mice) show a marked resistance to kainic acid (KA)-induced seizures, we investigated the behavioral response to KA in En1Cre/+; tOtx2ov/+ and control mice. No difference was observed between mutant and control mice, but En1Cre/+; tOtx2ov/+ mice showed a markedly different c-fos mRNA induction profile in the cerebral cortex and hippocampus after KA seizures, as compared to controls. Accordingly, an increased density of parvalbumin (PV)-positive inhibitory interneurons was detected in the deep layers of the frontal cortex of naive En1Cre/+; tOtx2ov/+ mice, as compared to controls. These data indicate that Otx2 overexpression results in increased DAergic innervation and PV cell density in the fronto-parietal cortex, with important consequences on spontaneous locomotor activity and seizure-induced gene expression. Our results strengthen the notion that Otx2 mutant mouse models are a powerful genetic tool to unravel the molecular and behavioral consequences of altered development of the DAergic system.
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the Transcription Factor Otx2 regulates choroid plexus development and function
Development, 2013Co-Authors: Pia A Johansson, Martin Irmler, Dario Acampora, Johannes Beckers, Antonio Simeone, Magdalena GotzAbstract:The choroid plexuses (ChPs) are the main regulators of cerebrospinal fluid (CSF) composition and thereby also control the composition of a principal source of signaling molecules that is in direct contact with neural stem cells in the developing brain. The regulators of ChP development mediating the acquisition of a fate that differs from the neighboring neuroepithelial cells are poorly understood. Here, we demonstrate in mice a crucial role for the Transcription Factor Otx2 in the development and maintenance of ChP cells. Deletion of Otx2 by the Otx2-CreERT2 driver line at E9 resulted in a lack of all ChPs, whereas deletion by the Gdf7-Cre driver line affected predominately the hindbrain ChP, which was reduced in size, primarily owing to an increase in apoptosis upon Otx2 deletion. Strikingly, Otx2 was still required for the maintenance of hindbrain ChP cells at later stages when Otx2 deletion was induced at E15, demonstrating a central role of Otx2 in ChP development and maintenance. Moreover, the predominant defects in the hindbrain ChP mediated by Gdf7-Cre deletion of Otx2 revealed its key role in regulating early CSF composition, which was altered in protein content, including the levels of Wnt4 and the Wnt modulator Tgm2. Accordingly, proliferation and Wnt signaling levels were increased in the distant cerebral cortex, suggesting a role of the hindbrain ChP in regulating CSF composition, including key signaling molecules. Thus, Otx2 acts as a master regulator of ChP development, thereby influencing one of the principal sources of signaling in the developing brain, the CSF.
Luca Giovanni Giovannantonio - One of the best experts on this subject based on the ideXlab platform.
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Otx2 expression is restricted to dopaminergic neurons of the ventral tegmental area in the adult brain.
The International Journal of Developmental Biology, 2020Co-Authors: Michela Salvio, Dario Acampora, Luca Giovanni Giovannantonio, Daniela Omodei, Antonio SimeoneAbstract:Mesencephalic-diencephalic dopaminergic (mdDA) neurons control motor, sensorimotor and motivated behaviour and their degeneration or abnormal functioning is associated with important pathologies, such as Parkinson’s disease and psychiatric disorders. Despite great efforts, the molecular basis and the genetic Factors differentially controlling identity, survival and vulnerability to neurodegeneration of mdDA neurons of the substantia nigra (SN) and ventral tegmental area (VTA) are poorly understood. We have previously shown that the Transcription Factor Otx2 is required for identity, fate and proliferation of mesencephalic DA (mesDA) progenitors. By using mouse models and immunohistochemistry, we have investigated whether Otx2 is expressed also in post-mitotic mdDA neurons. Our data reveal that Otx2 is expressed in post-mitotic mesDA neurons during mid-late gestation and in the adult brain. Remarkably, Otx2 expression is sharply excluded from mdDA neurons of the SN and is restricted to a relevant fraction of VTA neurons. Otx2+-TH+ neurons are concentrated to the ventral part of the VTA. Combined expression with other regionalized VTA markers shows that Otx2+-TH+ neurons are prevalently Girk2- and Calb+ and among these, those located in the medial and ventralmost portion of the VTA are also Ahd2+. These findings indicate that Otx2 represents the first Transcription Factor with a proven role in mdDA neurogenesis whose expression discriminates between SN and a relevant proportion of VTA neurons. This supports the possibility that Otx2 may act as a post-mitotic selector controlling functional features (e.g. identity and/or survival) of a relevant fraction of VTA neurons in the adult.
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Otx2 cell autonomously determines dorsal mesencephalon versus cerebellum fate independently of isthmic organizing activity
Development, 2014Co-Authors: Luca Giovanni Giovannantonio, Dario Acampora, Michela Salvio, Daniela Omodei, Nilima Prakash, Wolfgang Wurst, Alessandra Pierani, Antonio SimeoneAbstract:During embryonic development, the rostral neuroectoderm is regionalized into broad areas that are subsequently subdivided into progenitor compartments with specialized identity and fate. These events are controlled by signals emitted by organizing centers and interpreted by target progenitors, which activate superimposing waves of intrinsic Factors restricting their identity and fate. The Transcription Factor Otx2 plays a crucial role in mesencephalic development by positioning the midbrain-hindbrain boundary (MHB) and its organizing activity. Here, we investigated whether Otx2 is cell-autonomously required to control identity and fate of dorsal mesencephalic progenitors. With this aim, we have inactivated Otx2 in the Pax7 + dorsal mesencephalic domain, previously named m1, without affecting MHB integrity. We found that the Pax7 + m1 domain can be further subdivided into a dorsal Zic1 + m1a and a ventral Zic1 - m1b sub-domain. Loss of Otx2 in the m1a (Pax7 + Zic1 + ) sub-domain impairs the identity and fate of progenitors, which undergo a full switch into a coordinated cerebellum differentiation program. By contrast, in the m1b sub-domain (Pax7 + Zic1 - ) Otx2 is prevalently required for post-mitotic transition of mesencephalic GABAergic precursors. Moreover, genetic cell fate, BrdU cell labeling and Otx2 conditional inactivation experiments indicate that in Otx2 mutants all ectopic cerebellar cell types, including external granule cell layer (EGL) precursors, originate from the m1a progenitor sub-domain and that reprogramming of mesencephalic precursors into EGL or cerebellar GABAergic progenitors depends on temporal sensitivity to Otx2 ablation. Together, these findings indicate that Otx2 intrinsically controls different aspects of dorsal mesencephalic neurogenesis. In this context, Otx2 is cell-autonomously required in the m1a sub-domain to suppress cerebellar fate and promote mesencephalic differentiation independently of the MHB organizing activity.
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Otx2 selectively controls the neurogenesis of specific neuronal subtypes of the ventral tegmental area and compensates En1-dependent neuronal loss and MPTP vulnerability
Developmental Biology, 2012Co-Authors: Luca Giovanni Giovannantonio, Dario Acampora, Michela Salvio, Nilima Prakash, Wolfgang Wurst, Antonio SimeoneAbstract:Abstract Understanding the molecular basis underlying the neurogenesis of mesencephalic–diencephalic Dopaminergic (mdDA) neurons is a major task fueled by their relevance in controlling locomotor activity and emotion and their involvement in neurodegenerative and psychiatric diseases. Increasing evidence suggests that mdDA neurons of the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) represent two main distinct neuronal populations, which, in turn, include specific neuronal subsets. Relevant studies provided important results on mdDA neurogenesis, but, nevertheless, have not yet clarified how the identity of mdDA neuronal subtypes is established and, in particular, whether neurogenic Factors may direct progenitors towards the differentiation of specific mdDA neuronal subclasses. The Transcription Factor Otx2 is required for the neurogenesis of mesencephalic DA (mesDA) neurons and to control neuron subtype identity and sensitivity to the MPTP neurotoxin in the adult VTA. Here we studied whether Otx2 is required in mdDA progenitors for the generation of specific mdDA neuronal subtypes. We found that although expressed in virtually all mdDA progenitors, Otx2 is required selectively for the differentiation of VTA neuronal subtypes expressing Ahd2 and/or Calb but not for those co-expressing Girk2 and glyco-Dat. Moreover, mild over-expression of Otx2 in SNpc progenitors and neurons is sufficient to rescue En1 haploinsufficiency-dependent defects, such as progressive loss and increased MPTP sensitivity of SNpc neurons. Collectively, these data suggest that mdDA progenitors exhibit differential sensitivity to Otx2, which selectively influences the generation of a large and specific subset of VTA neurons. In addition, these data suggest that Otx2 and En1 may share similar properties and control survival and vulnerability to MPTP neurotoxin respectively in VTA and SNpc.
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The Role of Otx2 in Adult Mesencephalic–Diencephalic Dopaminergic Neurons
Molecular Neurobiology, 2011Co-Authors: Antonio Simeone, Dario Acampora, Michela Salvio, Luca Giovanni Giovannantonio, Daniela Omodei, Carmine TomasettiAbstract:Mesencephalic and diencephalic dopaminergic (mdDA) progenitors generate two major groups of neurons corresponding to the A9 neurons of the substantia nigra pars compacta (SNpc) and the A10 neurons of the ventral tegmental area (VTA). MdDA neurons control motor, sensorimotor and motivated behaviour and their degeneration or abnormal functioning is associated to Parkinson’s disease and psychiatric disorders. Although relevant advances have been made, the molecular basis controlling identity, survival and vulnerability to neurodegeneration of SNpc and VTA neurons remains poorly understood. Here, we will review recent findings on the role exerted by the Transcription Factor Otx2 in adult mdDA neurons. Otx2 expression is restricted to a relevant fraction of VTA neurons and absent in the SNpc. In particular, Otx2 is prevalently excluded from neurons of the dorsal–lateral VTA, which expressed Girk2 and high level of the dopamine transporter (Dat). Loss and gain of function mouse models revealed that Otx2 controls neuron subtype identity by antagonizing molecular and functional features of the dorsal–lateral VTA such as Girk2 and Dat expression as well as vulnerability to the parkinsonian MPTP toxin. Furthermore, when ectopically expressed in the SNpc, Otx2 suppresses Dat expression and confers efficient neuroprotection to MPTP toxicity by suppressing efficient DA uptake.
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The role of Otx2 in adult mesencephalic-diencephalic dopaminergic neurons.
Molecular Neurobiology, 2010Co-Authors: Antonio Simeone, Dario Acampora, Michela Salvio, Luca Giovanni Giovannantonio, Daniela Omodei, Carmine TomasettiAbstract:Mesencephalic and diencephalic dopaminergic (mdDA) progenitors generate two major groups of neurons corresponding to the A9 neurons of the substantia nigra pars compacta (SNpc) and the A10 neurons of the ventral tegmental area (VTA). MdDA neurons control motor, sensorimotor and motivated behaviour and their degeneration or abnormal functioning is associated to Parkinson’s disease and psychiatric disorders. Although relevant advances have been made, the molecular basis controlling identity, survival and vulnerability to neurodegeneration of SNpc and VTA neurons remains poorly understood. Here, we will review recent findings on the role exerted by the Transcription Factor Otx2 in adult mdDA neurons. Otx2 expression is restricted to a relevant fraction of VTA neurons and absent in the SNpc. In particular, Otx2 is prevalently excluded from neurons of the dorsal–lateral VTA, which expressed Girk2 and high level of the dopamine transporter (Dat). Loss and gain of function mouse models revealed that Otx2 controls neuron subtype identity by antagonizing molecular and functional features of the dorsal–lateral VTA such as Girk2 and Dat expression as well as vulnerability to the parkinsonian MPTP toxin. Furthermore, when ectopically expressed in the SNpc, Otx2 suppresses Dat expression and confers efficient neuroprotection to MPTP toxicity by suppressing efficient DA uptake.
Thomas Lamonerie - One of the best experts on this subject based on the ideXlab platform.
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Otx2 ChIP-seq Reveals Unique and Redundant Functions in the Mature Mouse Retina
PLOS ONE, 2014Co-Authors: Alexander Samuel, Michael Housset, Bruno Fant, Thomas LamonerieAbstract:During mouse retinal development and into adulthood, the Transcription Factor Otx2 is expressed in pigment epithelium, photoreceptors and bipolar cells. In the mature retina, Otx2 ablation causes photoreceptor degeneration through a non-cell-autonomous mechanism involving Otx2 function in the supporting RPE. Surprisingly, photoreceptor survival does not require Otx2 expression in the neural retina, where the related Crx homeobox gene, a major regulator of photoreceptor development, is also expressed. To get a deeper view of mouse Otx2 activities in the neural retina, we performed chromatin-immunoprecipitation followed by massively parallel sequencing (ChIP-seq) on Otx2. Using two independent ChIP-seq assays, we identified consistent sets of Otx2-bound cis-regulatory elements. Comparison with our previous RPE-specific Otx2 ChIP-seq data shows that Otx2 occupies different functional domains of the genome in RPE cells and in neural retina cells and regulates mostly different sets of genes. To assess the potential redundancy of Otx2 and Crx, we compared our data with Crx ChIP-seq data. While Crx genome occupancy markedly differs from Otx2 genome occupancy in the RPE, it largely overlaps that of Otx2 in the neural retina. Thus, in accordance with its essential role in the RPE and its non-essential role in the neural retina, Otx2 regulates different gene sets in the RPE and the neural retina, and shares an important part of its repertoire with Crx in the neural retina. Overall, this study provides a better understanding of gene-regulatory networks controlling photoreceptor homeostasis and disease.
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A new GFP-tagged line reveals unexpected Otx2 protein localization in retinal photoreceptors.
BMC Developmental Biology, 2007Co-Authors: Nicolas Fossat, Coralie Le Greneur, Francis Beby, Stéphane D. Vincent, Pierre Godement, Gilles Chatelain, Thomas LamonerieAbstract:Background Dynamic monitoring of protein expression and localization is fundamental to the understanding of biological processes. The paired-class homeodomain-containing Transcription Factor Otx2 is essential for normal head and brain development in vertebrates. Recent conditional knockout studies have pointed to multiple roles of this protein during late development and post-natal life. Yet, later expression and functions remain poorly characterized as specific reagents to detect the protein at any stage of development are still missing.
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A new GFP-tagged line reveals unexpected Otx2 protein localization in retinal photoreceptors
BMC Developmental Biology, 2007Co-Authors: Nicolas Fossat, Coralie Le Greneur, Francis Beby, Pierre Godement, Gilles Chatelain, Stéphane Vincent, Thomas LamonerieAbstract:Background Dynamic monitoring of protein expression and localization is fundamental to the understanding of biological processes. The paired-class homeodomain-containing Transcription Factor Otx2 is essential for normal head and brain development in vertebrates. Recent conditional knockout studies have pointed to multiple roles of this protein during late development and post-natal life. Yet, later expression and functions remain poorly characterized as specific reagents to detect the protein at any stage of development are still missing. Results We generated a new mouse line harbouring an insertion of the GFP gene within the Otx2 coding sequence to monitor the gene activity while preserving most of its functions. Our results demonstrate that this line represents a convenient tool to capture the dynamics of Otx2 gene expression from early embryonic stages to adulthood. In addition, we could visualize the intracellular location of Otx2 protein. In the retina, we reinterpret the former view of protein distribution and show a further level of regulation of intranuclear protein localization, which depends on the cell type. Conclusion The GFP-tagged Otx2 mouse line fully recapitulates previously known expression patterns and brings additional accuracy and easiness of detection of Otx2 gene activity. This opens up the way to live imaging of a highly dynamic actor of brain development and can be adapted to any mutant background to probe for genetic interaction between Otx2 and the mutated gene.
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Molecular dissection reveals decreased activity and not dominant negative effect in human Otx2 mutants
Journal of Molecular Medicine, 2006Co-Authors: Gilles Chatelain, Nicolas Fossat, Gilbert Brun, Thomas LamonerieAbstract:The paired-type homeodomain Transcription Factor Otx2 is essential for forebrain and eye development. Severe ocular malformations in humans have recently been associated with heterozygous Otx2 mutations. To document the molecular defects in human mutants, Otx2 structural characterization was carried out. A collection of deletion and point mutants was created to perform transactivation, DNA binding, and subcellular localization analyses. Transactivation was ascribed to both N- and C-termini of the protein, and DNA binding to the minimal homeodomain, where critical amino acid residues were identified. Acute nuclear localization appeared controlled by a nuclear localization sequence located within the homeodomain which acts in conjunction with a novel nuclear retention domain that we unraveled located in the central part of the protein. This region, which is poorly conserved among Otx proteins, was also endowed with dominant negative activity suggesting that it might confer unique properties to Otx2. Molecular diagnostic of human mutant Otx2 proteins discriminates hypomorphic and loss of function mutations from other mutations that may not be relevant to ocular pathology.
Michela Salvio - One of the best experts on this subject based on the ideXlab platform.
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Otx2 expression is restricted to dopaminergic neurons of the ventral tegmental area in the adult brain.
The International Journal of Developmental Biology, 2020Co-Authors: Michela Salvio, Dario Acampora, Luca Giovanni Giovannantonio, Daniela Omodei, Antonio SimeoneAbstract:Mesencephalic-diencephalic dopaminergic (mdDA) neurons control motor, sensorimotor and motivated behaviour and their degeneration or abnormal functioning is associated with important pathologies, such as Parkinson’s disease and psychiatric disorders. Despite great efforts, the molecular basis and the genetic Factors differentially controlling identity, survival and vulnerability to neurodegeneration of mdDA neurons of the substantia nigra (SN) and ventral tegmental area (VTA) are poorly understood. We have previously shown that the Transcription Factor Otx2 is required for identity, fate and proliferation of mesencephalic DA (mesDA) progenitors. By using mouse models and immunohistochemistry, we have investigated whether Otx2 is expressed also in post-mitotic mdDA neurons. Our data reveal that Otx2 is expressed in post-mitotic mesDA neurons during mid-late gestation and in the adult brain. Remarkably, Otx2 expression is sharply excluded from mdDA neurons of the SN and is restricted to a relevant fraction of VTA neurons. Otx2+-TH+ neurons are concentrated to the ventral part of the VTA. Combined expression with other regionalized VTA markers shows that Otx2+-TH+ neurons are prevalently Girk2- and Calb+ and among these, those located in the medial and ventralmost portion of the VTA are also Ahd2+. These findings indicate that Otx2 represents the first Transcription Factor with a proven role in mdDA neurogenesis whose expression discriminates between SN and a relevant proportion of VTA neurons. This supports the possibility that Otx2 may act as a post-mitotic selector controlling functional features (e.g. identity and/or survival) of a relevant fraction of VTA neurons in the adult.
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Otx2 cell autonomously determines dorsal mesencephalon versus cerebellum fate independently of isthmic organizing activity
Development, 2014Co-Authors: Luca Giovanni Giovannantonio, Dario Acampora, Michela Salvio, Daniela Omodei, Nilima Prakash, Wolfgang Wurst, Alessandra Pierani, Antonio SimeoneAbstract:During embryonic development, the rostral neuroectoderm is regionalized into broad areas that are subsequently subdivided into progenitor compartments with specialized identity and fate. These events are controlled by signals emitted by organizing centers and interpreted by target progenitors, which activate superimposing waves of intrinsic Factors restricting their identity and fate. The Transcription Factor Otx2 plays a crucial role in mesencephalic development by positioning the midbrain-hindbrain boundary (MHB) and its organizing activity. Here, we investigated whether Otx2 is cell-autonomously required to control identity and fate of dorsal mesencephalic progenitors. With this aim, we have inactivated Otx2 in the Pax7 + dorsal mesencephalic domain, previously named m1, without affecting MHB integrity. We found that the Pax7 + m1 domain can be further subdivided into a dorsal Zic1 + m1a and a ventral Zic1 - m1b sub-domain. Loss of Otx2 in the m1a (Pax7 + Zic1 + ) sub-domain impairs the identity and fate of progenitors, which undergo a full switch into a coordinated cerebellum differentiation program. By contrast, in the m1b sub-domain (Pax7 + Zic1 - ) Otx2 is prevalently required for post-mitotic transition of mesencephalic GABAergic precursors. Moreover, genetic cell fate, BrdU cell labeling and Otx2 conditional inactivation experiments indicate that in Otx2 mutants all ectopic cerebellar cell types, including external granule cell layer (EGL) precursors, originate from the m1a progenitor sub-domain and that reprogramming of mesencephalic precursors into EGL or cerebellar GABAergic progenitors depends on temporal sensitivity to Otx2 ablation. Together, these findings indicate that Otx2 intrinsically controls different aspects of dorsal mesencephalic neurogenesis. In this context, Otx2 is cell-autonomously required in the m1a sub-domain to suppress cerebellar fate and promote mesencephalic differentiation independently of the MHB organizing activity.
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Otx2 selectively controls the neurogenesis of specific neuronal subtypes of the ventral tegmental area and compensates En1-dependent neuronal loss and MPTP vulnerability
Developmental Biology, 2012Co-Authors: Luca Giovanni Giovannantonio, Dario Acampora, Michela Salvio, Nilima Prakash, Wolfgang Wurst, Antonio SimeoneAbstract:Abstract Understanding the molecular basis underlying the neurogenesis of mesencephalic–diencephalic Dopaminergic (mdDA) neurons is a major task fueled by their relevance in controlling locomotor activity and emotion and their involvement in neurodegenerative and psychiatric diseases. Increasing evidence suggests that mdDA neurons of the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) represent two main distinct neuronal populations, which, in turn, include specific neuronal subsets. Relevant studies provided important results on mdDA neurogenesis, but, nevertheless, have not yet clarified how the identity of mdDA neuronal subtypes is established and, in particular, whether neurogenic Factors may direct progenitors towards the differentiation of specific mdDA neuronal subclasses. The Transcription Factor Otx2 is required for the neurogenesis of mesencephalic DA (mesDA) neurons and to control neuron subtype identity and sensitivity to the MPTP neurotoxin in the adult VTA. Here we studied whether Otx2 is required in mdDA progenitors for the generation of specific mdDA neuronal subtypes. We found that although expressed in virtually all mdDA progenitors, Otx2 is required selectively for the differentiation of VTA neuronal subtypes expressing Ahd2 and/or Calb but not for those co-expressing Girk2 and glyco-Dat. Moreover, mild over-expression of Otx2 in SNpc progenitors and neurons is sufficient to rescue En1 haploinsufficiency-dependent defects, such as progressive loss and increased MPTP sensitivity of SNpc neurons. Collectively, these data suggest that mdDA progenitors exhibit differential sensitivity to Otx2, which selectively influences the generation of a large and specific subset of VTA neurons. In addition, these data suggest that Otx2 and En1 may share similar properties and control survival and vulnerability to MPTP neurotoxin respectively in VTA and SNpc.
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The Role of Otx2 in Adult Mesencephalic–Diencephalic Dopaminergic Neurons
Molecular Neurobiology, 2011Co-Authors: Antonio Simeone, Dario Acampora, Michela Salvio, Luca Giovanni Giovannantonio, Daniela Omodei, Carmine TomasettiAbstract:Mesencephalic and diencephalic dopaminergic (mdDA) progenitors generate two major groups of neurons corresponding to the A9 neurons of the substantia nigra pars compacta (SNpc) and the A10 neurons of the ventral tegmental area (VTA). MdDA neurons control motor, sensorimotor and motivated behaviour and their degeneration or abnormal functioning is associated to Parkinson’s disease and psychiatric disorders. Although relevant advances have been made, the molecular basis controlling identity, survival and vulnerability to neurodegeneration of SNpc and VTA neurons remains poorly understood. Here, we will review recent findings on the role exerted by the Transcription Factor Otx2 in adult mdDA neurons. Otx2 expression is restricted to a relevant fraction of VTA neurons and absent in the SNpc. In particular, Otx2 is prevalently excluded from neurons of the dorsal–lateral VTA, which expressed Girk2 and high level of the dopamine transporter (Dat). Loss and gain of function mouse models revealed that Otx2 controls neuron subtype identity by antagonizing molecular and functional features of the dorsal–lateral VTA such as Girk2 and Dat expression as well as vulnerability to the parkinsonian MPTP toxin. Furthermore, when ectopically expressed in the SNpc, Otx2 suppresses Dat expression and confers efficient neuroprotection to MPTP toxicity by suppressing efficient DA uptake.
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The role of Otx2 in adult mesencephalic-diencephalic dopaminergic neurons.
Molecular Neurobiology, 2010Co-Authors: Antonio Simeone, Dario Acampora, Michela Salvio, Luca Giovanni Giovannantonio, Daniela Omodei, Carmine TomasettiAbstract:Mesencephalic and diencephalic dopaminergic (mdDA) progenitors generate two major groups of neurons corresponding to the A9 neurons of the substantia nigra pars compacta (SNpc) and the A10 neurons of the ventral tegmental area (VTA). MdDA neurons control motor, sensorimotor and motivated behaviour and their degeneration or abnormal functioning is associated to Parkinson’s disease and psychiatric disorders. Although relevant advances have been made, the molecular basis controlling identity, survival and vulnerability to neurodegeneration of SNpc and VTA neurons remains poorly understood. Here, we will review recent findings on the role exerted by the Transcription Factor Otx2 in adult mdDA neurons. Otx2 expression is restricted to a relevant fraction of VTA neurons and absent in the SNpc. In particular, Otx2 is prevalently excluded from neurons of the dorsal–lateral VTA, which expressed Girk2 and high level of the dopamine transporter (Dat). Loss and gain of function mouse models revealed that Otx2 controls neuron subtype identity by antagonizing molecular and functional features of the dorsal–lateral VTA such as Girk2 and Dat expression as well as vulnerability to the parkinsonian MPTP toxin. Furthermore, when ectopically expressed in the SNpc, Otx2 suppresses Dat expression and confers efficient neuroprotection to MPTP toxicity by suppressing efficient DA uptake.