M. Barallobre - Academia.edu (original) (raw)

Papers by M. Barallobre

Research paper thumbnail of Vascular endothelial growth factor receptor 3 directly regulates murine neurogenesis

Genes & Development, 2011

Neural stem cells (NSCs) are slowly dividing astrocytes that are intimately associated with capil... more Neural stem cells (NSCs) are slowly dividing astrocytes that are intimately associated with capillary endothelial cells in the subventricular zone (SVZ) of the brain. Functionally, members of the vascular endothelial growth factor (VEGF) family can stimulate neurogenesis as well as angiogenesis, but it has been unclear whether they act directly via VEGF receptors (VEGFRs) expressed by neural cells, or indirectly via the release of growth factors from angiogenic capillaries. Here, we show that VEGFR-3, a receptor required for lymphangiogenesis, is expressed by NSCs and is directly required for neurogenesis. Vegfr3:YFP reporter mice show VEGFR-3 expression in multipotent NSCs, which are capable of self-renewal and are activated by the VEGFR-3 ligand VEGF-C in vitro. Overexpression of VEGF-C stimulates VEGFR-3-expressing NSCs and neurogenesis in the SVZ without affecting angiogenesis. Conversely, conditional deletion of Vegfr3 in neural cells, inducible deletion in subventricular astro...

Research paper thumbnail of DYRK1A promotes dopaminergic neuron survival in the developing brain and in a mouse model of Parkinson's disease

Cell death & disease, 2014

In the brain, programmed cell death (PCD) serves to adjust the numbers of the different types of ... more In the brain, programmed cell death (PCD) serves to adjust the numbers of the different types of neurons during development, and its pathological reactivation in the adult leads to neurodegeneration. Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) is a pleiotropic kinase involved in neural proliferation and cell death, and its role during brain growth is evolutionarily conserved. Human DYRK1A lies in the Down syndrome critical region on chromosome 21, and heterozygous mutations in the gene cause microcephaly and neurological dysfunction. The mouse model for DYRK1A haploinsufficiency (the Dyrk1a(+/-) mouse) presents neuronal deficits in specific regions of the adult brain, including the substantia nigra (SN), although the mechanisms underlying these pathogenic effects remain unclear. Here we study the effect of DYRK1A copy number variation on dopaminergic cell homeostasis. We show that mesencephalic DA (mDA) neurons are generated in the embryo at normal rat...

Research paper thumbnail of Aberrant development of hippocampal circuits and altered neural activity in netrin 1-deficient mice

Development, 2000

Diffusible factors, including netrins and semaphorins, are believed to be important cues for the ... more Diffusible factors, including netrins and semaphorins, are believed to be important cues for the formation of neural circuits in the forebrain. Here we have examined the role of netrin 1 in the development of hippocampal connections. We show that netrin 1 and its receptor, Dcc, are expressed in the developing fimbria and in projection neurons, respectively, and that netrin 1 promotes the outgrowth of hippocampal axons in vitro via DCC receptors. We also show that the hippocampus of netrin 1-deficient mice shows a misorientation of fiber tracts and pathfinding errors, as detected with antibodies against the surface proteins TAG-1, L1 and DCC. DiI injections show that hippocampal commissural axons do not cross the midline in these mutants. Instead, when axons approach the midline, they turn ventrally and form a massive aberrant projection to the ipsilateral septum. In addition, both the ipsilateral entorhino-hippocampal and the CA3-to-CA1 associational projections show an altered patt...

Research paper thumbnail of Aberrant development of hippocampal circuits and altered neural activity in netrin 1-deficient mice

Development, 2000

Diffusible factors, including netrins and semaphorins, are believed to be important cues for the ... more Diffusible factors, including netrins and semaphorins, are believed to be important cues for the formation of neural circuits in the forebrain. Here we have examined the role of netrin 1 in the development of hippocampal connections. We show that netrin 1 and its receptor, Dcc, are expressed in the developing fimbria and in projection neurons, respectively, and that netrin 1 promotes the outgrowth of hippocampal axons in vitro via DCC receptors. We also show that the hippocampus of netrin 1-deficient mice shows a misorientation of fiber tracts and pathfinding errors, as detected with antibodies against the surface proteins TAG-1, L1 and DCC. DiI injections show that hippocampal commissural axons do not cross the midline in these mutants. Instead, when axons approach the midline, they turn ventrally and form a massive aberrant projection to the ipsilateral septum. In addition, both the ipsilateral entorhino-hippocampal and the CA3-to-CA1 associational projections show an altered patt...

Research paper thumbnail of Dyrk1A gene dosage controls developmental cell death of the mesencephalic dopaminergic neurons

International Journal of Developmental Neuroscience, 2010

We have studied CD38, Cx43 expression in rat brain cells after perinatal hypoxic-ischemic injury.... more We have studied CD38, Cx43 expression in rat brain cells after perinatal hypoxic-ischemic injury. We found regulation of CD38 by modulators of metabolism of endogenous retinoic acid or by exogenous retinoic acid and Cx43 by glycirretinoic acid. Possibility to use the data for development of pharmacological method of neuroprotection is discussed. To elicit hypoxic-ischemic perinatal brain injury, 7-day-old perinatal (P7) rats (n = 40) were subjected to right carotid artery ligation followed 1 h of 8% oxygen exposure (Rice J., 1981). Control animals (n = 20) were sham-operated. Biological material (front and occipital brain areas) was taken away in 4, 8, 72 hours, 10 days after the operation for preparing frozen slices. Expression of CD38, Cx43, GFAP, MAP2, modulation of Cx43 activity in astrocytes by 5 M glycirretinoic acid (GRA), modulation of CD38 in vivo by retinoic acid (RA) (20 mg/kg), fluorimetric measurement of CD38 were done. CD38 expression after hypoxic-ischemic brain damage raises 8 h after brain injury following by reducing in P17 to control meanings. The amount of Cx43 + and GFAP + cells increases in acute period of hypoxia, what attracted Cx43 +-astrocytes enhancement in damage area. On postischemic 10th day 80% of Cx43 +-cells and 42% of GFAP + cells are CD38-immunopositive, but amount of MAP2 + cells reduces as well as number of MAP2 + CD38 + neurons. Cx43 inhibitor GRA reduces ADP-ribosyl cyclase activity. RA decreases CD38 expression in astrocytes. Acute period of perinatal hypoxic/ischemic brain injury attends by reactive astrogliosis, change of CD38 and Cx43 expression in astrocytes is marker of neuroglial interactions disturbances after perinatal CNS injury, modulation of which by RA regulators and GRA make a base for new therapeutic neuroprotective strategy at perinatal period.

Research paper thumbnail of The protein kinase Dyrk1A regulates cell number during the development of the central nervous system

International Journal of Developmental Neuroscience, 2008

Research paper thumbnail of Triplication of DYRK1A causes retinal structural and functional alterations in Down syndrome

Human Molecular Genetics, 2013

Down syndrome (DS) results from the triplication of approximately 300 human chromosome 21 (Hsa21)... more Down syndrome (DS) results from the triplication of approximately 300 human chromosome 21 (Hsa21) genes and affects almost all body organs. Children with DS have defects in visual processing that may have a negative impact on their daily life and cognitive development. However, there is little known about the genes and pathogenesis underlying these defects. Here, we show morphometric in vivo data indicating that the neural retina is thicker in DS individuals than in the normal population. A similar thickening specifically affecting the inner part of the retina was also observed in a trisomic model of DS, the Ts65Dn mouse. Increased retinal size and cellularity in this model correlated with abnormal retinal function and resulted from an impaired caspase-9-mediated apoptosis during development. Moreover, we show that mice bearing only one additional copy of Dyrk1a have the same retinal phenotype as Ts65Dn mice and normalization of Dyrk1a gene copy number in Ts65Dn mice completely rescues both, morphological and functional phenotypes. Thus, triplication of Dyrk1a is necessary and sufficient to cause the retinal phenotype described in the trisomic model. Our data demonstrate for the first time the implication of DYRK1A overexpression in a developmental alteration of the central nervous system associated with DS, thereby providing insights into the aetiology of neurosensorial dysfunction in a complex disease.

Research paper thumbnail of DYRK1A promotes dopaminergic neuron survival in the developing brain and in a mouse model of Parkinson's disease

Cell death & disease, 2014

In the brain, programmed cell death (PCD) serves to adjust the numbers of the different types of ... more In the brain, programmed cell death (PCD) serves to adjust the numbers of the different types of neurons during development, and its pathological reactivation in the adult leads to neurodegeneration. Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) is a pleiotropic kinase involved in neural proliferation and cell death, and its role during brain growth is evolutionarily conserved. Human DYRK1A lies in the Down syndrome critical region on chromosome 21, and heterozygous mutations in the gene cause microcephaly and neurological dysfunction. The mouse model for DYRK1A haploinsufficiency (the Dyrk1a(+/-) mouse) presents neuronal deficits in specific regions of the adult brain, including the substantia nigra (SN), although the mechanisms underlying these pathogenic effects remain unclear. Here we study the effect of DYRK1A copy number variation on dopaminergic cell homeostasis. We show that mesencephalic DA (mDA) neurons are generated in the embryo at normal rat...

Research paper thumbnail of Vascular endothelial growth factor receptor 3 directly regulates murine neurogenesis

Genes & Development, 2011

Neural stem cells (NSCs) are slowly dividing astrocytes that are intimately associated with capil... more Neural stem cells (NSCs) are slowly dividing astrocytes that are intimately associated with capillary endothelial cells in the subventricular zone (SVZ) of the brain. Functionally, members of the vascular endothelial growth factor (VEGF) family can stimulate neurogenesis as well as angiogenesis, but it has been unclear whether they act directly via VEGF receptors (VEGFRs) expressed by neural cells, or indirectly via the release of growth factors from angiogenic capillaries. Here, we show that VEGFR-3, a receptor required for lymphangiogenesis, is expressed by NSCs and is directly required for neurogenesis. Vegfr3:YFP reporter mice show VEGFR-3 expression in multipotent NSCs, which are capable of self-renewal and are activated by the VEGFR-3 ligand VEGF-C in vitro. Overexpression of VEGF-C stimulates VEGFR-3-expressing NSCs and neurogenesis in the SVZ without affecting angiogenesis. Conversely, conditional deletion of Vegfr3 in neural cells, inducible deletion in subventricular astro...

Research paper thumbnail of DYRK1A promotes dopaminergic neuron survival in the developing brain and in a mouse model of Parkinson's disease

Cell death & disease, 2014

In the brain, programmed cell death (PCD) serves to adjust the numbers of the different types of ... more In the brain, programmed cell death (PCD) serves to adjust the numbers of the different types of neurons during development, and its pathological reactivation in the adult leads to neurodegeneration. Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) is a pleiotropic kinase involved in neural proliferation and cell death, and its role during brain growth is evolutionarily conserved. Human DYRK1A lies in the Down syndrome critical region on chromosome 21, and heterozygous mutations in the gene cause microcephaly and neurological dysfunction. The mouse model for DYRK1A haploinsufficiency (the Dyrk1a(+/-) mouse) presents neuronal deficits in specific regions of the adult brain, including the substantia nigra (SN), although the mechanisms underlying these pathogenic effects remain unclear. Here we study the effect of DYRK1A copy number variation on dopaminergic cell homeostasis. We show that mesencephalic DA (mDA) neurons are generated in the embryo at normal rat...

Research paper thumbnail of Aberrant development of hippocampal circuits and altered neural activity in netrin 1-deficient mice

Development, 2000

Diffusible factors, including netrins and semaphorins, are believed to be important cues for the ... more Diffusible factors, including netrins and semaphorins, are believed to be important cues for the formation of neural circuits in the forebrain. Here we have examined the role of netrin 1 in the development of hippocampal connections. We show that netrin 1 and its receptor, Dcc, are expressed in the developing fimbria and in projection neurons, respectively, and that netrin 1 promotes the outgrowth of hippocampal axons in vitro via DCC receptors. We also show that the hippocampus of netrin 1-deficient mice shows a misorientation of fiber tracts and pathfinding errors, as detected with antibodies against the surface proteins TAG-1, L1 and DCC. DiI injections show that hippocampal commissural axons do not cross the midline in these mutants. Instead, when axons approach the midline, they turn ventrally and form a massive aberrant projection to the ipsilateral septum. In addition, both the ipsilateral entorhino-hippocampal and the CA3-to-CA1 associational projections show an altered patt...

Research paper thumbnail of Aberrant development of hippocampal circuits and altered neural activity in netrin 1-deficient mice

Development, 2000

Diffusible factors, including netrins and semaphorins, are believed to be important cues for the ... more Diffusible factors, including netrins and semaphorins, are believed to be important cues for the formation of neural circuits in the forebrain. Here we have examined the role of netrin 1 in the development of hippocampal connections. We show that netrin 1 and its receptor, Dcc, are expressed in the developing fimbria and in projection neurons, respectively, and that netrin 1 promotes the outgrowth of hippocampal axons in vitro via DCC receptors. We also show that the hippocampus of netrin 1-deficient mice shows a misorientation of fiber tracts and pathfinding errors, as detected with antibodies against the surface proteins TAG-1, L1 and DCC. DiI injections show that hippocampal commissural axons do not cross the midline in these mutants. Instead, when axons approach the midline, they turn ventrally and form a massive aberrant projection to the ipsilateral septum. In addition, both the ipsilateral entorhino-hippocampal and the CA3-to-CA1 associational projections show an altered patt...

Research paper thumbnail of Dyrk1A gene dosage controls developmental cell death of the mesencephalic dopaminergic neurons

International Journal of Developmental Neuroscience, 2010

We have studied CD38, Cx43 expression in rat brain cells after perinatal hypoxic-ischemic injury.... more We have studied CD38, Cx43 expression in rat brain cells after perinatal hypoxic-ischemic injury. We found regulation of CD38 by modulators of metabolism of endogenous retinoic acid or by exogenous retinoic acid and Cx43 by glycirretinoic acid. Possibility to use the data for development of pharmacological method of neuroprotection is discussed. To elicit hypoxic-ischemic perinatal brain injury, 7-day-old perinatal (P7) rats (n = 40) were subjected to right carotid artery ligation followed 1 h of 8% oxygen exposure (Rice J., 1981). Control animals (n = 20) were sham-operated. Biological material (front and occipital brain areas) was taken away in 4, 8, 72 hours, 10 days after the operation for preparing frozen slices. Expression of CD38, Cx43, GFAP, MAP2, modulation of Cx43 activity in astrocytes by 5 M glycirretinoic acid (GRA), modulation of CD38 in vivo by retinoic acid (RA) (20 mg/kg), fluorimetric measurement of CD38 were done. CD38 expression after hypoxic-ischemic brain damage raises 8 h after brain injury following by reducing in P17 to control meanings. The amount of Cx43 + and GFAP + cells increases in acute period of hypoxia, what attracted Cx43 +-astrocytes enhancement in damage area. On postischemic 10th day 80% of Cx43 +-cells and 42% of GFAP + cells are CD38-immunopositive, but amount of MAP2 + cells reduces as well as number of MAP2 + CD38 + neurons. Cx43 inhibitor GRA reduces ADP-ribosyl cyclase activity. RA decreases CD38 expression in astrocytes. Acute period of perinatal hypoxic/ischemic brain injury attends by reactive astrogliosis, change of CD38 and Cx43 expression in astrocytes is marker of neuroglial interactions disturbances after perinatal CNS injury, modulation of which by RA regulators and GRA make a base for new therapeutic neuroprotective strategy at perinatal period.

Research paper thumbnail of The protein kinase Dyrk1A regulates cell number during the development of the central nervous system

International Journal of Developmental Neuroscience, 2008

Research paper thumbnail of Triplication of DYRK1A causes retinal structural and functional alterations in Down syndrome

Human Molecular Genetics, 2013

Down syndrome (DS) results from the triplication of approximately 300 human chromosome 21 (Hsa21)... more Down syndrome (DS) results from the triplication of approximately 300 human chromosome 21 (Hsa21) genes and affects almost all body organs. Children with DS have defects in visual processing that may have a negative impact on their daily life and cognitive development. However, there is little known about the genes and pathogenesis underlying these defects. Here, we show morphometric in vivo data indicating that the neural retina is thicker in DS individuals than in the normal population. A similar thickening specifically affecting the inner part of the retina was also observed in a trisomic model of DS, the Ts65Dn mouse. Increased retinal size and cellularity in this model correlated with abnormal retinal function and resulted from an impaired caspase-9-mediated apoptosis during development. Moreover, we show that mice bearing only one additional copy of Dyrk1a have the same retinal phenotype as Ts65Dn mice and normalization of Dyrk1a gene copy number in Ts65Dn mice completely rescues both, morphological and functional phenotypes. Thus, triplication of Dyrk1a is necessary and sufficient to cause the retinal phenotype described in the trisomic model. Our data demonstrate for the first time the implication of DYRK1A overexpression in a developmental alteration of the central nervous system associated with DS, thereby providing insights into the aetiology of neurosensorial dysfunction in a complex disease.

Research paper thumbnail of DYRK1A promotes dopaminergic neuron survival in the developing brain and in a mouse model of Parkinson's disease

Cell death & disease, 2014

In the brain, programmed cell death (PCD) serves to adjust the numbers of the different types of ... more In the brain, programmed cell death (PCD) serves to adjust the numbers of the different types of neurons during development, and its pathological reactivation in the adult leads to neurodegeneration. Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) is a pleiotropic kinase involved in neural proliferation and cell death, and its role during brain growth is evolutionarily conserved. Human DYRK1A lies in the Down syndrome critical region on chromosome 21, and heterozygous mutations in the gene cause microcephaly and neurological dysfunction. The mouse model for DYRK1A haploinsufficiency (the Dyrk1a(+/-) mouse) presents neuronal deficits in specific regions of the adult brain, including the substantia nigra (SN), although the mechanisms underlying these pathogenic effects remain unclear. Here we study the effect of DYRK1A copy number variation on dopaminergic cell homeostasis. We show that mesencephalic DA (mDA) neurons are generated in the embryo at normal rat...