The Experts below are selected from a list of 54 Experts worldwide ranked by ideXlab platform
Alexandra L. Joyner - One of the best experts on this subject based on the ideXlab platform.
-
Genetic deletion of genes in the cerebellar rhombic lip lineage can stimulate compensation through adaptive reprogramming of ventricular zone-derived progenitors
Neural Development, 2019Co-Authors: Alexandre Wojcinski, Morgane Morabito, Andrew K. Lawton, Daniel N. Stephen, Alexandra L. JoynerAbstract:Background The Cerebellum is a foliated posterior brain structure involved in coordination of motor movements and cognition. The Cerebellum undergoes rapid growth postnataly due to Sonic Hedgehog (SHH) signaling-dependent proliferation of ATOH1+ granule cell precursors (GCPs) in the external granule cell layer (EGL), a key step for generating cerebellar foliation and the correct number of granule cells. Due to its late development, the Cerebellum is particularly vulnerable to injury from preterm birth and stress around birth. We recently uncovered an intrinsic capacity of the developing Cerebellum to replenish ablated GCPs via adaptive reprogramming of Nestin-expressing progenitors (NEPs). However, whether this compensation mechanism occurs in mouse mutants affecting the developing Cerebellum and could lead to mis-interpretation of phenotypes was not known. Methods We used two different approaches to remove the main SHH signaling activator GLI2 in GCPs: 1) Our mosaic mutant analysis with spatial and temporal control of recombination (MASTR) technique to delete Gli2 in a small subset of GCPs; 2) An Atoh1-Cre transgene to delete Gli2 in most of the EGL. Genetic Inducible Fate Mapping (GIFM) and live imaging were used to analyze the behavior of NEPs after Gli2 deletion. Results Mosaic analysis demonstrated that SHH-GLI2 signaling is critical for generating the correct pool of granule cells by maintaining GCPs in an undifferentiated proliferative state and promoting their survival. Despite this, inactivation of GLI2 in a large proportion of GCPs in the embryo did not lead to the expected dramatic reduction in the size of the adult Cerebellum. GIFM uncovered that NEPs do indeed replenish GCPs in Gli2 conditional mutants, and then expand and partially restore the production of granule cells. Furthermore, the SHH signaling-dependent NEP compensation requires Gli2 , demonstrating that the activator side of the pathway is involved. Conclusion We demonstrate that a mouse conditional mutation that results in loss of SHH signaling in GCPs is not sufficient to induce long term severe Cerebellum Hypoplasia. The ability of the neonatal Cerebellum to regenerate after loss of cells via a response by NEPs must therefore be considered when interpreting the phenotypes of Atoh1-Cre conditional mutants affecting GCPs.
-
Genetic deletion of genes in the cerebellar rhombic lip lineage can stimulate compensation through adaptive reprogramming of ventricular zone-derived progenitors
Neural Development, 2019Co-Authors: Alexandre Wojcinski, Morgane Morabito, Andrew K. Lawton, Daniel Stephen, Alexandra L. JoynerAbstract:The Cerebellum is a foliated posterior brain structure involved in coordination of motor movements and cognition. The Cerebellum undergoes rapid growth postnataly due to Sonic Hedgehog (SHH) signaling-dependent proliferation of ATOH1+ granule cell precursors (GCPs) in the external granule cell layer (EGL), a key step for generating cerebellar foliation and the correct number of granule cells. Due to its late development, the Cerebellum is particularly vulnerable to injury from preterm birth and stress around birth. We recently uncovered an intrinsic capacity of the developing Cerebellum to replenish ablated GCPs via adaptive reprogramming of Nestin-expressing progenitors (NEPs). However, whether this compensation mechanism occurs in mouse mutants affecting the developing Cerebellum and could lead to mis-interpretation of phenotypes was not known. We used two different approaches to remove the main SHH signaling activator GLI2 in GCPs: 1) Our mosaic mutant analysis with spatial and temporal control of recombination (MASTR) technique to delete Gli2 in a small subset of GCPs; 2) An Atoh1-Cre transgene to delete Gli2 in most of the EGL. Genetic Inducible Fate Mapping (GIFM) and live imaging were used to analyze the behavior of NEPs after Gli2 deletion. Mosaic analysis demonstrated that SHH-GLI2 signaling is critical for generating the correct pool of granule cells by maintaining GCPs in an undifferentiated proliferative state and promoting their survival. Despite this, inactivation of GLI2 in a large proportion of GCPs in the embryo did not lead to the expected dramatic reduction in the size of the adult Cerebellum. GIFM uncovered that NEPs do indeed replenish GCPs in Gli2 conditional mutants, and then expand and partially restore the production of granule cells. Furthermore, the SHH signaling-dependent NEP compensation requires Gli2, demonstrating that the activator side of the pathway is involved. We demonstrate that a mouse conditional mutation that results in loss of SHH signaling in GCPs is not sufficient to induce long term severe Cerebellum Hypoplasia. The ability of the neonatal Cerebellum to regenerate after loss of cells via a response by NEPs must therefore be considered when interpreting the phenotypes of Atoh1-Cre conditional mutants affecting GCPs.
-
Genetic deletion of genes in the cerebellar rhombic lip lineage can stimulate compensation through adaptive reprogramming of ventricular zone-derived progenitors
bioRxiv, 2018Co-Authors: Alexandre Wojcinski, Morgane Morabito, Andrew K. Lawton, Daniel Stephen, Alexandra L. JoynerAbstract:Background: The Cerebellum is a foliated posterior brain structure involved in coordination of motor movements and cognition. The Cerebellum undergoes rapid growth postnataly due to Sonic Hedgehog (SHH) signaling-dependent proliferation of ATOH1+ granule cell precursors (GCPs) in the external granule cell layer (EGL), a key step for generating cerebellar foliation and the correct number of granule cells. Due to its late development, the Cerebellum is particularly vulnerable to injury from preterm birth and stress around birth. We recently uncovered an intrinsic capacity of the developing Cerebellum to replenish ablated GCPs via adaptive reprogramming of Nestin-expressing progenitors (NEPs). However, whether this compensation mechanism occurs in mouse mutants affecting the developing Cerebellum and could lead to mis-interpretation of phenotypes was not known. Methods: We used two different approaches to remove the main SHH signaling activator GLI2 in GCPs: 1) our mosaic mutant analysis with spatial and temporal control of recombination (MASTR) technique to delete Gli2 in a small subset of GCPs; 2) An Atoh1-Cre transgene to delete Gli2 in most of the EGL. Genetic Inducible Fate Mapping (GIFM) and live imaging were used to analyze the behavior of NEPs after Gli2 deletion. Results: Mosaic analysis demonstrated that SHH-GLI2 signaling is critical for generating the correct pool of granule cells by maintaining GCPs in an undifferentiated proliferative state and promoting their survival. Despite this, inactivation of GLI2 in a large proportion of GCPs in the embryo did not lead to the expected dramatic reduction in the size of the adult Cerebellum. GIFM uncovered that NEPs do indeed replenish GCPs in Gli2 conditional mutants, and then expand and partially restore the production of granule cells. Furthermore, the SHH signaling-dependent NEP compensation requires Gli2, demonstrating that the activator side of the pathway is involved. Conclusion: We demonstrate that a mouse conditional mutation that results in loss of SHH signaling in GCPs is not sufficient to induce long term severe Cerebellum Hypoplasia. The ability of the neonatal Cerebellum to regenerate after loss of cells via a response by NEPs must therefore be considered when interpreting the phenotypes of conditional mutants affecting GCPs.
Erik T. Te Beek - One of the best experts on this subject based on the ideXlab platform.
-
tRNA splicing endonuclease mutations cause pontocerebellar Hypoplasia
Nature Genetics, 2008Co-Authors: Birgit Budde, Yasmin Namavar, Peter G. Barth, Bwee Tien Poll-the, Gudrun Nürnberg, Christian Becker, Fred Van Ruissen, Marian A. J. Weterman, Kees Fluiter, Erik T. Te BeekAbstract:Pontocerebellar Hypoplasias (PCH) represent a group of neurodegenerative autosomal recessive disorders with prenatal onset, atrophy or Hypoplasia of the Cerebellum, Hypoplasia of the ventral pons, microcephaly, variable neocortical atrophy and severe mental and motor impairments. In two subtypes, PCH2 and PCH4, we identified mutations in three of the four different subunits of the tRNA-splicing endonuclease complex. Our findings point to RNA processing as a new basic cellular impairment in neurological disorders. Frank Baas and colleagues report mutations in three of the four subunits of the tRNA-splicing endonuclease complex in families with two subtypes of pontocerebellar Hypoplasia. The findings implicate tRNA processing in neurological disorders.
-
tRNA splicing endonuclease mutations cause pontocerebellar Hypoplasia
Nature Genetics, 2008Co-Authors: Birgit Budde, Yasmin Namavar, Peter G. Barth, Bwee Tien Poll-the, Gudrun Nürnberg, Christian Becker, Fred Van Ruissen, Marian A. J. Weterman, Kees Fluiter, Erik T. Te BeekAbstract:Pontocerebellar Hypoplasias (PCH) represent a group of neurodegenerative autosomal recessive disorders with prenatal onset, atrophy or Hypoplasia of the Cerebellum, Hypoplasia of the ventral pons, microcephaly, variable neocortical atrophy and severe mental and motor impairments. In two subtypes, PCH2 and PCH4, we identified mutations in three of the four different subunits of the tRNA-splicing endonuclease complex. Our findings point to RNA processing as a new basic cellular impairment in neurological disorders.
Alexandre Wojcinski - One of the best experts on this subject based on the ideXlab platform.
-
Genetic deletion of genes in the cerebellar rhombic lip lineage can stimulate compensation through adaptive reprogramming of ventricular zone-derived progenitors
Neural Development, 2019Co-Authors: Alexandre Wojcinski, Morgane Morabito, Andrew K. Lawton, Daniel N. Stephen, Alexandra L. JoynerAbstract:Background The Cerebellum is a foliated posterior brain structure involved in coordination of motor movements and cognition. The Cerebellum undergoes rapid growth postnataly due to Sonic Hedgehog (SHH) signaling-dependent proliferation of ATOH1+ granule cell precursors (GCPs) in the external granule cell layer (EGL), a key step for generating cerebellar foliation and the correct number of granule cells. Due to its late development, the Cerebellum is particularly vulnerable to injury from preterm birth and stress around birth. We recently uncovered an intrinsic capacity of the developing Cerebellum to replenish ablated GCPs via adaptive reprogramming of Nestin-expressing progenitors (NEPs). However, whether this compensation mechanism occurs in mouse mutants affecting the developing Cerebellum and could lead to mis-interpretation of phenotypes was not known. Methods We used two different approaches to remove the main SHH signaling activator GLI2 in GCPs: 1) Our mosaic mutant analysis with spatial and temporal control of recombination (MASTR) technique to delete Gli2 in a small subset of GCPs; 2) An Atoh1-Cre transgene to delete Gli2 in most of the EGL. Genetic Inducible Fate Mapping (GIFM) and live imaging were used to analyze the behavior of NEPs after Gli2 deletion. Results Mosaic analysis demonstrated that SHH-GLI2 signaling is critical for generating the correct pool of granule cells by maintaining GCPs in an undifferentiated proliferative state and promoting their survival. Despite this, inactivation of GLI2 in a large proportion of GCPs in the embryo did not lead to the expected dramatic reduction in the size of the adult Cerebellum. GIFM uncovered that NEPs do indeed replenish GCPs in Gli2 conditional mutants, and then expand and partially restore the production of granule cells. Furthermore, the SHH signaling-dependent NEP compensation requires Gli2 , demonstrating that the activator side of the pathway is involved. Conclusion We demonstrate that a mouse conditional mutation that results in loss of SHH signaling in GCPs is not sufficient to induce long term severe Cerebellum Hypoplasia. The ability of the neonatal Cerebellum to regenerate after loss of cells via a response by NEPs must therefore be considered when interpreting the phenotypes of Atoh1-Cre conditional mutants affecting GCPs.
-
Genetic deletion of genes in the cerebellar rhombic lip lineage can stimulate compensation through adaptive reprogramming of ventricular zone-derived progenitors
Neural Development, 2019Co-Authors: Alexandre Wojcinski, Morgane Morabito, Andrew K. Lawton, Daniel Stephen, Alexandra L. JoynerAbstract:The Cerebellum is a foliated posterior brain structure involved in coordination of motor movements and cognition. The Cerebellum undergoes rapid growth postnataly due to Sonic Hedgehog (SHH) signaling-dependent proliferation of ATOH1+ granule cell precursors (GCPs) in the external granule cell layer (EGL), a key step for generating cerebellar foliation and the correct number of granule cells. Due to its late development, the Cerebellum is particularly vulnerable to injury from preterm birth and stress around birth. We recently uncovered an intrinsic capacity of the developing Cerebellum to replenish ablated GCPs via adaptive reprogramming of Nestin-expressing progenitors (NEPs). However, whether this compensation mechanism occurs in mouse mutants affecting the developing Cerebellum and could lead to mis-interpretation of phenotypes was not known. We used two different approaches to remove the main SHH signaling activator GLI2 in GCPs: 1) Our mosaic mutant analysis with spatial and temporal control of recombination (MASTR) technique to delete Gli2 in a small subset of GCPs; 2) An Atoh1-Cre transgene to delete Gli2 in most of the EGL. Genetic Inducible Fate Mapping (GIFM) and live imaging were used to analyze the behavior of NEPs after Gli2 deletion. Mosaic analysis demonstrated that SHH-GLI2 signaling is critical for generating the correct pool of granule cells by maintaining GCPs in an undifferentiated proliferative state and promoting their survival. Despite this, inactivation of GLI2 in a large proportion of GCPs in the embryo did not lead to the expected dramatic reduction in the size of the adult Cerebellum. GIFM uncovered that NEPs do indeed replenish GCPs in Gli2 conditional mutants, and then expand and partially restore the production of granule cells. Furthermore, the SHH signaling-dependent NEP compensation requires Gli2, demonstrating that the activator side of the pathway is involved. We demonstrate that a mouse conditional mutation that results in loss of SHH signaling in GCPs is not sufficient to induce long term severe Cerebellum Hypoplasia. The ability of the neonatal Cerebellum to regenerate after loss of cells via a response by NEPs must therefore be considered when interpreting the phenotypes of Atoh1-Cre conditional mutants affecting GCPs.
-
Genetic deletion of genes in the cerebellar rhombic lip lineage can stimulate compensation through adaptive reprogramming of ventricular zone-derived progenitors
bioRxiv, 2018Co-Authors: Alexandre Wojcinski, Morgane Morabito, Andrew K. Lawton, Daniel Stephen, Alexandra L. JoynerAbstract:Background: The Cerebellum is a foliated posterior brain structure involved in coordination of motor movements and cognition. The Cerebellum undergoes rapid growth postnataly due to Sonic Hedgehog (SHH) signaling-dependent proliferation of ATOH1+ granule cell precursors (GCPs) in the external granule cell layer (EGL), a key step for generating cerebellar foliation and the correct number of granule cells. Due to its late development, the Cerebellum is particularly vulnerable to injury from preterm birth and stress around birth. We recently uncovered an intrinsic capacity of the developing Cerebellum to replenish ablated GCPs via adaptive reprogramming of Nestin-expressing progenitors (NEPs). However, whether this compensation mechanism occurs in mouse mutants affecting the developing Cerebellum and could lead to mis-interpretation of phenotypes was not known. Methods: We used two different approaches to remove the main SHH signaling activator GLI2 in GCPs: 1) our mosaic mutant analysis with spatial and temporal control of recombination (MASTR) technique to delete Gli2 in a small subset of GCPs; 2) An Atoh1-Cre transgene to delete Gli2 in most of the EGL. Genetic Inducible Fate Mapping (GIFM) and live imaging were used to analyze the behavior of NEPs after Gli2 deletion. Results: Mosaic analysis demonstrated that SHH-GLI2 signaling is critical for generating the correct pool of granule cells by maintaining GCPs in an undifferentiated proliferative state and promoting their survival. Despite this, inactivation of GLI2 in a large proportion of GCPs in the embryo did not lead to the expected dramatic reduction in the size of the adult Cerebellum. GIFM uncovered that NEPs do indeed replenish GCPs in Gli2 conditional mutants, and then expand and partially restore the production of granule cells. Furthermore, the SHH signaling-dependent NEP compensation requires Gli2, demonstrating that the activator side of the pathway is involved. Conclusion: We demonstrate that a mouse conditional mutation that results in loss of SHH signaling in GCPs is not sufficient to induce long term severe Cerebellum Hypoplasia. The ability of the neonatal Cerebellum to regenerate after loss of cells via a response by NEPs must therefore be considered when interpreting the phenotypes of conditional mutants affecting GCPs.
Birgit Budde - One of the best experts on this subject based on the ideXlab platform.
-
tRNA splicing endonuclease mutations cause pontocerebellar Hypoplasia
Nature Genetics, 2008Co-Authors: Birgit Budde, Yasmin Namavar, Peter G. Barth, Bwee Tien Poll-the, Gudrun Nürnberg, Christian Becker, Fred Van Ruissen, Marian A. J. Weterman, Kees Fluiter, Erik T. Te BeekAbstract:Pontocerebellar Hypoplasias (PCH) represent a group of neurodegenerative autosomal recessive disorders with prenatal onset, atrophy or Hypoplasia of the Cerebellum, Hypoplasia of the ventral pons, microcephaly, variable neocortical atrophy and severe mental and motor impairments. In two subtypes, PCH2 and PCH4, we identified mutations in three of the four different subunits of the tRNA-splicing endonuclease complex. Our findings point to RNA processing as a new basic cellular impairment in neurological disorders. Frank Baas and colleagues report mutations in three of the four subunits of the tRNA-splicing endonuclease complex in families with two subtypes of pontocerebellar Hypoplasia. The findings implicate tRNA processing in neurological disorders.
-
tRNA splicing endonuclease mutations cause pontocerebellar Hypoplasia
Nature Genetics, 2008Co-Authors: Birgit Budde, Yasmin Namavar, Peter G. Barth, Bwee Tien Poll-the, Gudrun Nürnberg, Christian Becker, Fred Van Ruissen, Marian A. J. Weterman, Kees Fluiter, Erik T. Te BeekAbstract:Pontocerebellar Hypoplasias (PCH) represent a group of neurodegenerative autosomal recessive disorders with prenatal onset, atrophy or Hypoplasia of the Cerebellum, Hypoplasia of the ventral pons, microcephaly, variable neocortical atrophy and severe mental and motor impairments. In two subtypes, PCH2 and PCH4, we identified mutations in three of the four different subunits of the tRNA-splicing endonuclease complex. Our findings point to RNA processing as a new basic cellular impairment in neurological disorders.
Yasmin Namavar - One of the best experts on this subject based on the ideXlab platform.
-
Mutations of TSEN and CASK genes are prevalent in pontocerebellar Hypoplasias type 2 and 4
Brain, 2011Co-Authors: Yasmin Namavar, Peter G. Barth, Frank Baas, Bwee Tien Poll-theAbstract:Sir, Pontocerebellar Hypoplasias (PCH) represent a group of neurodegenerative autosomal recessive disorders with prenatal onset, atrophy or Hypoplasia of the Cerebellum, Hypoplasia of the ventral pons, microcephaly, variable neocortical atrophy and severe mental and motor impairments (Barth, 2000). Recently in two subtypes, PCH type 2 (associated with dyskinesia and/or dystonia and variable degrees of spasticity) and PCH type 4 (a more severe phenotype associated with perinatal symptoms, ventilator dependency and early death), mutations have been identified in three of the four different subunits of the transfer RNA-splicing endonuclease complex ( TSEN54 , TSEN34 and TSEN2 ) (Budde et al. , 2008). Mutations in the calcium/calmodulin-dependent serine protein kinase ( CASK ) gene have also been associated with X-linked mental retardation (XLMR) with microcephaly, optic atrophy and brainstem and cerebellar Hypoplasia (Najm et al. , 2008). Namavar et al. (2011) reported on a series of 169 patients affected with PCH and identified mutations in TSEN54 or RARS2 genes in 106 individuals. The authors display a strong correlation between TSEN54 mutations and a ‘dragonfly-like’ cerebellar pattern on magnetic resonance imaging, in which the cerebellar hemispheres are flat and severely reduced in size and the vermis is relatively spared. They also show that homozygosity for the common …
-
Impairment of the tRNA-splicing endonuclease subunit 54 (tsen54) gene causes neurological abnormalities and larval death in zebrafish models of pontocerebellar Hypoplasia
Human Molecular Genetics, 2011Co-Authors: Paul R. Kasher, Yasmin Namavar, Kees Fluiter, Paula Van Tijn, Aleksander Sizarov, Maarten Kamermans, Andrew J. Grierson, Danica Zivkovic, Frank BaasAbstract:Pontocerebellar Hypoplasia (PCH) represents a group (PCH1-6) of neurodegenerative autosomal recessive disorders characterized by Hypoplasia and/or atrophy of the Cerebellum, Hypoplasia of the ventral pons, progressive microcephaly and variable neocortical atrophy. The majority of PCH2 and PCH4 cases are caused by mutations in the TSEN54 gene; one of the four subunits comprising the tRNA-splicing endonuclease (TSEN) complex. We hypothesized that TSEN54 mutations act through a loss of function mechanism. At 8 weeks of gestation, human TSEN54 is expressed ubiquitously in the brain, yet strong expression is seen within the telencephalon and metencephalon. Comparable expression patterns for tsen54 are observed in zebrafish embryos. Morpholino (MO) knockdown of tsen54 in zebrafish embryos results in loss of structural definition in the brain. This phenotype was partially rescued by co-injecting the MO with human TSEN54 mRNA. A developmental patterning defect was not associated with tsen54 knockdown; however, an increase in cell death within the brain was observed, thus bearing resemblance to PCH pathophysiology. Additionally, N-methyl-N-nitrosourea mutant zebrafish homozygous for a tsen54 premature stop-codon mutation die within 9 days post-fertilization. To determine whether a common disease pathway exists between TSEN54 and other PCH-related genes, we also monitored the effects of mitochondrial arginyl-tRNA synthetase (rars2; PCH1 and PCH6) knockdown in zebrafish. Comparable brain phenotypes were observed following the inhibition of both genes. These data strongly support the hypothesis that TSEN54 mutations cause PCH through a loss of function mechanism. Also we suggest that a common disease pathway may exist between TSEN54- and RARS2-related PCH, which may involve a tRNA processing-related mechanism.
-
tRNA splicing endonuclease mutations cause pontocerebellar Hypoplasia
Nature Genetics, 2008Co-Authors: Birgit Budde, Yasmin Namavar, Peter G. Barth, Bwee Tien Poll-the, Gudrun Nürnberg, Christian Becker, Fred Van Ruissen, Marian A. J. Weterman, Kees Fluiter, Erik T. Te BeekAbstract:Pontocerebellar Hypoplasias (PCH) represent a group of neurodegenerative autosomal recessive disorders with prenatal onset, atrophy or Hypoplasia of the Cerebellum, Hypoplasia of the ventral pons, microcephaly, variable neocortical atrophy and severe mental and motor impairments. In two subtypes, PCH2 and PCH4, we identified mutations in three of the four different subunits of the tRNA-splicing endonuclease complex. Our findings point to RNA processing as a new basic cellular impairment in neurological disorders. Frank Baas and colleagues report mutations in three of the four subunits of the tRNA-splicing endonuclease complex in families with two subtypes of pontocerebellar Hypoplasia. The findings implicate tRNA processing in neurological disorders.
-
tRNA splicing endonuclease mutations cause pontocerebellar Hypoplasia
Nature Genetics, 2008Co-Authors: Birgit Budde, Yasmin Namavar, Peter G. Barth, Bwee Tien Poll-the, Gudrun Nürnberg, Christian Becker, Fred Van Ruissen, Marian A. J. Weterman, Kees Fluiter, Erik T. Te BeekAbstract:Pontocerebellar Hypoplasias (PCH) represent a group of neurodegenerative autosomal recessive disorders with prenatal onset, atrophy or Hypoplasia of the Cerebellum, Hypoplasia of the ventral pons, microcephaly, variable neocortical atrophy and severe mental and motor impairments. In two subtypes, PCH2 and PCH4, we identified mutations in three of the four different subunits of the tRNA-splicing endonuclease complex. Our findings point to RNA processing as a new basic cellular impairment in neurological disorders.