The Experts below are selected from a list of 7599 Experts worldwide ranked by ideXlab platform
Rolf Kemler - One of the best experts on this subject based on the ideXlab platform.
-
inactivation of the beta catenin gene by wnt1 cre mediated deletion results in dramatic Brain Malformation and failure of craniofacial development
Development, 2001Co-Authors: Veronique Brault, Robert Moore, Stefanie Kutsch, Makoto Ishibashi, David H Rowitch, Andrew P Mcmahon, Lukas Sommer, Oreda Boussadia, Rolf KemlerAbstract:beta-Catenin is a central component of both the cadherin-catenin cell adhesion complex and the Wnt signaling pathway. We have investigated the role of beta-catenin during Brain morphogenesis, by specifically inactivating the beta-catenin gene in the region of Wnt1 expression. To achieve this, mice with a conditional ('floxed') allele of beta-catenin with required exons flanked by loxP recombination sequences were intercrossed with transgenic mice that expressed Cre recombinase under control of Wnt1 regulatory sequences. beta-Catenin gene deletion resulted in dramatic Brain Malformation and failure of craniofacial development. Absence of part of the midBrain and all of the cerebellum is reminiscent of the conventional Wnt1 knockout (Wnt1(-/-)), suggesting that Wnt1 acts through beta-catenin in controlling midBrain-hindBrain development. The craniofacial phenotype, not observed in embryos that lack Wnt1, indicates a role for beta-catenin in the fate of neural crest cells. Analysis of neural tube explants shows that (beta-catenin is efficiently deleted in migrating neural crest cell precursors. This, together with an increased apoptosis in cells migrating to the cranial ganglia and in areas of prechondrogenic condensations, suggests that removal of beta-catenin affects neural crest cell survival and/or differentiation. Our results demonstrate the pivotal role of beta-catenin in morphogenetic processes during Brain and craniofacial development.
-
inactivation of the β catenin gene by wnt1 cre mediated deletion results in dramatic Brain Malformation and failure of craniofacial development
Development, 2001Co-Authors: Veronique Brault, Robert Moore, Stefanie Kutsch, Makoto Ishibashi, David H Rowitch, Andrew P Mcmahon, Lukas Sommer, Oreda Boussadia, Rolf KemlerAbstract:beta-Catenin is a central component of both the cadherin-catenin cell adhesion complex and the Wnt signaling pathway. We have investigated the role of beta-catenin during Brain morphogenesis, by specifically inactivating the beta-catenin gene in the region of Wnt1 expression. To achieve this, mice with a conditional ('floxed') allele of beta-catenin with required exons flanked by loxP recombination sequences were intercrossed with transgenic mice that expressed Cre recombinase under control of Wnt1 regulatory sequences. beta-Catenin gene deletion resulted in dramatic Brain Malformation and failure of craniofacial development. Absence of part of the midBrain and all of the cerebellum is reminiscent of the conventional Wnt1 knockout (Wnt1(-/-)), suggesting that Wnt1 acts through beta-catenin in controlling midBrain-hindBrain development. The craniofacial phenotype, not observed in embryos that lack Wnt1, indicates a role for beta-catenin in the fate of neural crest cells. Analysis of neural tube explants shows that (beta-catenin is efficiently deleted in migrating neural crest cell precursors. This, together with an increased apoptosis in cells migrating to the cranial ganglia and in areas of prechondrogenic condensations, suggests that removal of beta-catenin affects neural crest cell survival and/or differentiation. Our results demonstrate the pivotal role of beta-catenin in morphogenetic processes during Brain and craniofacial development.
-
inactivation of the β catenin gene by wnt1 cre mediated deletion results in dramatic Brain Malformation and failure of craniofacial development
Development, 2001Co-Authors: Veronique Brault, Robert Moore, Stefanie Kutsch, Makoto Ishibashi, David H Rowitch, Andrew P Mcmahon, Lukas Sommer, Oreda Boussadia, Rolf KemlerAbstract:('bgr;)-Catenin is a central component of both the cadherin-catenin cell adhesion complex and the Wnt signaling pathway. We have investigated the role of (β)-catenin during Brain morphogenesis, by specifically inactivating the (β)-catenin gene in the region of Wnt1 expression. To achieve this, mice with a conditional ('floxed') allele of (β)-catenin with required exons flanked by loxP recombination sequences were intercrossed with transgenic mice that expressed Cre recombinase under control of Wnt1 regulatory sequences. (β)-catenin gene deletion resulted in dramatic Brain Malformation and failure of craniofacial development. Absence of part of the midBrain and all of the cerebellum is reminiscent of the conventional Wnt1 knockout (Wnt1(−)(/)(−)), suggesting that Wnt1 acts through (β)-catenin in controlling midBrain-hindBrain development. The craniofacial phenotype, not observed in embryos that lack Wnt1, indicates a role for (β)-catenin in the fate of neural crest cells. Analysis of neural tube explants shows that (β)-catenin is efficiently deleted in migrating neural crest cell precursors. This, together with an increased apoptosis in cells migrating to the cranial ganglia and in areas of prechondrogenic condensations, suggests that removal of (β)-catenin affects neural crest cell survival and/or differentiation. Our results demonstrate the pivotal role of (β)-catenin in morphogenetic processes during Brain and craniofacial development.
-
inactivation of the beta catenin gene by wnt1 cre mediated deletion results in dramatic Brain Malformation and failure of craniofacial development
Development, 2001Co-Authors: Veronique Brault, Robert Moore, Stefanie Kutsch, Makoto Ishibashi, David H Rowitch, Andrew P Mcmahon, Lukas Sommer, Oreda Boussadia, Rolf KemlerAbstract:('bgr;)-Catenin is a central component of both the cadherin-catenin cell adhesion complex and the Wnt signaling pathway. We have investigated the role of (β)-catenin during Brain morphogenesis, by specifically inactivating the (β)-catenin gene in the region of Wnt1 expression. To achieve this, mice with a conditional ('floxed') allele of (β)-catenin with required exons flanked by loxP recombination sequences were intercrossed with transgenic mice that expressed Cre recombinase under control of Wnt1 regulatory sequences. (β)-catenin gene deletion resulted in dramatic Brain Malformation and failure of craniofacial development. Absence of part of the midBrain and all of the cerebellum is reminiscent of the conventional Wnt1 knockout (Wnt1(−)(/)(−)), suggesting that Wnt1 acts through (β)-catenin in controlling midBrain-hindBrain development. The craniofacial phenotype, not observed in embryos that lack Wnt1, indicates a role for (β)-catenin in the fate of neural crest cells. Analysis of neural tube explants shows that (β)-catenin is efficiently deleted in migrating neural crest cell precursors. This, together with an increased apoptosis in cells migrating to the cranial ganglia and in areas of prechondrogenic condensations, suggests that removal of (β)-catenin affects neural crest cell survival and/or differentiation. Our results demonstrate the pivotal role of (β)-catenin in morphogenetic processes during Brain and craniofacial development.
Richard I Gregory - One of the best experts on this subject based on the ideXlab platform.
-
mettl1 wdr4 mediated m7g trna methylome is required for normal mrna translation and embryonic stem cell self renewal and differentiation
Molecular Cell, 2018Co-Authors: Victor S Lelyveld, Junho Choe, Jack W Szostak, Richard I GregoryAbstract:Summary tRNAs are subject to numerous modifications, including methylation. Mutations in the human N7-methylguanosine (m7G) methyltransferase complex METTL1/WDR4 cause primordial dwarfism and Brain Malformation, yet the molecular and cellular function in mammals is not well understood. We developed m7G methylated tRNA immunoprecipitation sequencing (MeRIP-seq) and tRNA reduction and cleavage sequencing (TRAC-seq) to reveal the m7G tRNA methylome in mouse embryonic stem cells (mESCs). A subset of 22 tRNAs is modified at a "RAGGU" motif within the variable loop. We observe increased ribosome occupancy at the corresponding codons in Mettl1 knockout mESCs, implying widespread effects on tRNA function, ribosome pausing, and mRNA translation. Translation of cell cycle genes and those associated with Brain abnormalities is particularly affected. Mettl1 or Wdr4 knockout mESCs display defective self-renewal and neural differentiation. Our study uncovers the complexity of the mammalian m7G tRNA methylome and highlights its essential role in ESCs with links to human disease.
-
mettl1 wdr4 mediated m7g trna methylome is required for normal mrna translation and embryonic stem cell self renewal and differentiation
Molecular Cell, 2018Co-Authors: Shuibin Lin, Victor S Lelyveld, Junho Choe, Jack W Szostak, Qi Liu, Richard I GregoryAbstract:Summary tRNAs are subject to numerous modifications, including methylation. Mutations in the human N7-methylguanosine (m7G) methyltransferase complex METTL1/WDR4 cause primordial dwarfism and Brain Malformation, yet the molecular and cellular function in mammals is not well understood. We developed m7G methylated tRNA immunoprecipitation sequencing (MeRIP-seq) and tRNA reduction and cleavage sequencing (TRAC-seq) to reveal the m7G tRNA methylome in mouse embryonic stem cells (mESCs). A subset of 22 tRNAs is modified at a "RAGGU" motif within the variable loop. We observe increased ribosome occupancy at the corresponding codons in Mettl1 knockout mESCs, implying widespread effects on tRNA function, ribosome pausing, and mRNA translation. Translation of cell cycle genes and those associated with Brain abnormalities is particularly affected. Mettl1 or Wdr4 knockout mESCs display defective self-renewal and neural differentiation. Our study uncovers the complexity of the mammalian m7G tRNA methylome and highlights its essential role in ESCs with links to human disease.
William B Dobyns - One of the best experts on this subject based on the ideXlab platform.
-
rhombencephalosynapsis fused cerebellum confused geneticists
American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2018Co-Authors: Kimberly A Aldinger, Megan E Grout, Jennifer C Dempsey, Hannah M Tully, Michele G Mehaffey, William B Dobyns, Dan DohertyAbstract:Rhombencephalosynapsis (RES) is a unique cerebellar Malformation characterized by fusion of the cerebellar hemispheres with partial or complete absence of a recognizable cerebellar vermis. Subsets of patients also have other Brain Malformations such as midBrain fusion with aqueductal stenosis, characteristic craniofacial features (prominent forehead, flat midface, hypertelorism, ear abnormalities), and somatic Malformations (heart, kidney, spine and limb defects). Similar to known genetic Brain Malformations, the RES cerebellar Malformation is highly stereotyped, yet no genetic causes have not been identified. Here, we outline our current understanding of the genetic basis for RES, discuss limitations, and outline future approaches to identifying the causes of this fascinating Brain Malformation.
-
oculocerebrocutaneous syndrome the Brain Malformation defines a core phenotype
Journal of Medical Genetics, 2005Co-Authors: Ute Moog, Marilyn C Jones, Lynne M Bird, William B DobynsAbstract:Background: Oculocerebrocutaneous syndrome (OCCS) is characterised by orbital cysts and anophthalmia or microphthalmia, focal aplastic or hypoplastic skin defects, skin appendages, and Brain Malformations. The eye and skin abnormalities are well described but the neuropathological features less so. To date, 28 patients with an unequivocal diagnosis of OCCS have been reported, with a preponderance of males. Objective: To evaluate the Brain imaging studies, clinical records, photographs, and pathological material of two new and nine previously reported cases of OCCS. Results: There was a consistent pattern of Malformations in eight of the 11 cases, consisting of frontal predominant polymicrogyria and periventricular nodular heterotopia, enlarged lateral ventricles or hydrocephalus, agenesis of the corpus callosum sometimes associated with interhemispheric cysts, and a novel mid-hindBrain Malformation. The latter consisted of a giant and dysplastic tectum, absent cerebellar vermis, small cerebellar hemispheres in most cases, and a large posterior fossa fluid collection. Conclusions: The mid-hindBrain Malformation appears pathognomonic for OCCS. The eye and skin features of OCCS show considerable overlap with several other syndromes, such as encephalocraniocutaneous lipomatosis, oculo-auriculo-vertebral spectrum, and focal dermal hypoplasia, none of which has a comparable pattern of Brain Malformations. In particular the unique mid-hindBrain Malformation also distinguishes OCCS from related syndromes with comparable foreBrain anomalies. The pattern of Malformation described thus helps in differentiating OCCS from other entities. The mid-hindBrain Malformation points to a defect of the mid-hindBrain organiser as the underlying pathogenic mechanism.
-
bilateral frontal polymicrogyria a newly recognized Brain Malformation syndrome
Neurology, 2000Co-Authors: Renzo Guerrini, Laszlo Sztriha, James A Barkovich, William B DobynsAbstract:Background and Objective: Polymicrogyria is a Brain Malformation characterized by abnormal cortical lamination, excessive cortical folding, and fusion of the cortical molecular layer. Two distinct bilateral localized forms have been described: bilateral perisylvian polymicrogyria, which has proved to be genetically heterogeneous, and bilateral parasagittal parieto-occipital polymicrogyria, which has been described only in sporadic patients. We describe 13 patients with symmetric polymicrogyria of both frontal lobes back to the precentral sulcus: bilateral frontal polymicrogyria (BFP). Methods: Review of clinical records, Brain MRI, and EEG results of 13 patients; correlation with other regional polymicrogyrias. Results: The abnormal cortex extended from the frontal poles anteriorly to the precentral gyrus posteriorly and to the frontal operculum inferiorly and was relatively symmetric in all 13 patients. All patients presented with developmental delay and mild spastic quadriparesis, but variably impaired language development (12/13), mental retardation (11/13), and epilepsy (5/13) also occurred. BFP was sporadic in 13 of 13 patients, but 2 of 13 had consanguineous parents. Conclusions: BFP extends the spectrum of the recognized bilateral symmetric regional polymicrogyria syndromes.
-
lis1 and xlis dcx mutations cause most classical lissencephaly but different patterns of Malformation
Human Molecular Genetics, 1998Co-Authors: Daniela T Pilz, James A Barkovich, Christopher A Walsh, Naomichi Matsumoto, Sharon R Minnerath, Patti L Mills, Joseph G Gleeson, Kristin M Allen, William B DobynsAbstract:Classical lissencephaly (LIS) is a neuronal migration disorder resulting in Brain Malformation, epilepsy and mental retardation. Deletions or mutations of LIS1 on 17p13.3 and mutations in XLIS (DCX) on Xq22.3-q23 produce LIS. Direct DNA sequencing of LIS1 and XLIS was performed in 25 children with sporadic LIS and no deletion of LIS1 by fluorescence in situ hybridization. Mutations of LIS1 were found by sequencing (n = 8) and Southern blot (n = 2) in a total of 10 patients (40%) of both sexes and mutations of XLIS in five males (20%). Combined with previous data, deletions or mutations of these two genes account for ∼76% of isolated LIS. These data demonstrate that LIS1 and XLIS mutations cause the majority of, though not all, human LIS. The mutations in LIS1 were predicted to result in protein truncation in six of eight patients and splice site mutations in two, all of which disrupt one or more of the seven WD40 repeats contained in the LIS1 protein. Point mutations in XLIS identified the C-terminal serine/proline-rich region as potentially important for protein function. The patients with mutations were included in a genotype-phenotype analysis of 32 subjects with deletions or other mutations of these two genes. Whereas the Brain Malformation due to LIS1 mutations was more severe over the parietal and occipital regions, XLIS mutations produced the reverse gradient, which was more severe over the frontal cortex. The distinct LIS patterns suggest that LIS1 and XLIS may be part of overlapping, but distinct, signaling pathways that promote neuronal migration.
-
lis1 and xlis dcx mutations cause most classical lissencephaly but different patterns of Malformation
Human Molecular Genetics, 1998Co-Authors: Daniela T Pilz, James A Barkovich, Christopher A Walsh, Naomichi Matsumoto, Sharon R Minnerath, Patti L Mills, Joseph G Gleeson, Kristin M Allen, William B DobynsAbstract:Classical lissencephaly (LIS) is a neuronal migration disorder resulting in Brain Malformation, epilepsy and mental retardation. Deletions or mutations of LIS1 on 17p13.3 and mutations in XLIS ( DCX ) on Xq22.3-q23 produce LIS. Direct DNA sequencing of LIS1 and XLIS was performed in 25 children with sporadic LIS and no deletion of LIS1 by fluorescence in situ hybridization. Mutations of LIS1 were found by sequencing ( n = 8) and Southern blot ( n = 2) in a total of 10 patients (40%) of both sexes and mutations of XLIS in five males (20%). Combined with previous data, deletions or mutations of these two genes account for approximately 76% of isolated LIS. These data demonstrate that LIS1 and XLIS mutations cause the majority of, though not all, human LIS. The mutations in LIS1 were predicted to result in protein truncation in six of eight patients and splice site mutations in two, all of which disrupt one or more of the seven WD40 repeats contained in the LIS1 protein. Point mutations in XLIS identified the C-terminal serine/proline-rich region as potentially important for protein function. The patients with mutations were included in a genotype-phenotype analysis of 32 subjects with deletions or other mutations of these two genes. Whereas the Brain Malformation due to LIS1 mutations was more severe over the parietal and occipital regions, XLIS mutations produced the reverse gradient, which was more severe over the frontal cortex. The distinct LIS patterns suggest that LIS1 and XLIS may be part of overlapping, but distinct, signaling pathways that promote neuronal migration.
Junho Choe - One of the best experts on this subject based on the ideXlab platform.
-
mettl1 wdr4 mediated m7g trna methylome is required for normal mrna translation and embryonic stem cell self renewal and differentiation
Molecular Cell, 2018Co-Authors: Victor S Lelyveld, Junho Choe, Jack W Szostak, Richard I GregoryAbstract:Summary tRNAs are subject to numerous modifications, including methylation. Mutations in the human N7-methylguanosine (m7G) methyltransferase complex METTL1/WDR4 cause primordial dwarfism and Brain Malformation, yet the molecular and cellular function in mammals is not well understood. We developed m7G methylated tRNA immunoprecipitation sequencing (MeRIP-seq) and tRNA reduction and cleavage sequencing (TRAC-seq) to reveal the m7G tRNA methylome in mouse embryonic stem cells (mESCs). A subset of 22 tRNAs is modified at a "RAGGU" motif within the variable loop. We observe increased ribosome occupancy at the corresponding codons in Mettl1 knockout mESCs, implying widespread effects on tRNA function, ribosome pausing, and mRNA translation. Translation of cell cycle genes and those associated with Brain abnormalities is particularly affected. Mettl1 or Wdr4 knockout mESCs display defective self-renewal and neural differentiation. Our study uncovers the complexity of the mammalian m7G tRNA methylome and highlights its essential role in ESCs with links to human disease.
-
mettl1 wdr4 mediated m7g trna methylome is required for normal mrna translation and embryonic stem cell self renewal and differentiation
Molecular Cell, 2018Co-Authors: Shuibin Lin, Victor S Lelyveld, Junho Choe, Jack W Szostak, Qi Liu, Richard I GregoryAbstract:Summary tRNAs are subject to numerous modifications, including methylation. Mutations in the human N7-methylguanosine (m7G) methyltransferase complex METTL1/WDR4 cause primordial dwarfism and Brain Malformation, yet the molecular and cellular function in mammals is not well understood. We developed m7G methylated tRNA immunoprecipitation sequencing (MeRIP-seq) and tRNA reduction and cleavage sequencing (TRAC-seq) to reveal the m7G tRNA methylome in mouse embryonic stem cells (mESCs). A subset of 22 tRNAs is modified at a "RAGGU" motif within the variable loop. We observe increased ribosome occupancy at the corresponding codons in Mettl1 knockout mESCs, implying widespread effects on tRNA function, ribosome pausing, and mRNA translation. Translation of cell cycle genes and those associated with Brain abnormalities is particularly affected. Mettl1 or Wdr4 knockout mESCs display defective self-renewal and neural differentiation. Our study uncovers the complexity of the mammalian m7G tRNA methylome and highlights its essential role in ESCs with links to human disease.
Veronique Brault - One of the best experts on this subject based on the ideXlab platform.
-
inactivation of the beta catenin gene by wnt1 cre mediated deletion results in dramatic Brain Malformation and failure of craniofacial development
Development, 2001Co-Authors: Veronique Brault, Robert Moore, Stefanie Kutsch, Makoto Ishibashi, David H Rowitch, Andrew P Mcmahon, Lukas Sommer, Oreda Boussadia, Rolf KemlerAbstract:beta-Catenin is a central component of both the cadherin-catenin cell adhesion complex and the Wnt signaling pathway. We have investigated the role of beta-catenin during Brain morphogenesis, by specifically inactivating the beta-catenin gene in the region of Wnt1 expression. To achieve this, mice with a conditional ('floxed') allele of beta-catenin with required exons flanked by loxP recombination sequences were intercrossed with transgenic mice that expressed Cre recombinase under control of Wnt1 regulatory sequences. beta-Catenin gene deletion resulted in dramatic Brain Malformation and failure of craniofacial development. Absence of part of the midBrain and all of the cerebellum is reminiscent of the conventional Wnt1 knockout (Wnt1(-/-)), suggesting that Wnt1 acts through beta-catenin in controlling midBrain-hindBrain development. The craniofacial phenotype, not observed in embryos that lack Wnt1, indicates a role for beta-catenin in the fate of neural crest cells. Analysis of neural tube explants shows that (beta-catenin is efficiently deleted in migrating neural crest cell precursors. This, together with an increased apoptosis in cells migrating to the cranial ganglia and in areas of prechondrogenic condensations, suggests that removal of beta-catenin affects neural crest cell survival and/or differentiation. Our results demonstrate the pivotal role of beta-catenin in morphogenetic processes during Brain and craniofacial development.
-
inactivation of the β catenin gene by wnt1 cre mediated deletion results in dramatic Brain Malformation and failure of craniofacial development
Development, 2001Co-Authors: Veronique Brault, Robert Moore, Stefanie Kutsch, Makoto Ishibashi, David H Rowitch, Andrew P Mcmahon, Lukas Sommer, Oreda Boussadia, Rolf KemlerAbstract:beta-Catenin is a central component of both the cadherin-catenin cell adhesion complex and the Wnt signaling pathway. We have investigated the role of beta-catenin during Brain morphogenesis, by specifically inactivating the beta-catenin gene in the region of Wnt1 expression. To achieve this, mice with a conditional ('floxed') allele of beta-catenin with required exons flanked by loxP recombination sequences were intercrossed with transgenic mice that expressed Cre recombinase under control of Wnt1 regulatory sequences. beta-Catenin gene deletion resulted in dramatic Brain Malformation and failure of craniofacial development. Absence of part of the midBrain and all of the cerebellum is reminiscent of the conventional Wnt1 knockout (Wnt1(-/-)), suggesting that Wnt1 acts through beta-catenin in controlling midBrain-hindBrain development. The craniofacial phenotype, not observed in embryos that lack Wnt1, indicates a role for beta-catenin in the fate of neural crest cells. Analysis of neural tube explants shows that (beta-catenin is efficiently deleted in migrating neural crest cell precursors. This, together with an increased apoptosis in cells migrating to the cranial ganglia and in areas of prechondrogenic condensations, suggests that removal of beta-catenin affects neural crest cell survival and/or differentiation. Our results demonstrate the pivotal role of beta-catenin in morphogenetic processes during Brain and craniofacial development.
-
inactivation of the β catenin gene by wnt1 cre mediated deletion results in dramatic Brain Malformation and failure of craniofacial development
Development, 2001Co-Authors: Veronique Brault, Robert Moore, Stefanie Kutsch, Makoto Ishibashi, David H Rowitch, Andrew P Mcmahon, Lukas Sommer, Oreda Boussadia, Rolf KemlerAbstract:('bgr;)-Catenin is a central component of both the cadherin-catenin cell adhesion complex and the Wnt signaling pathway. We have investigated the role of (β)-catenin during Brain morphogenesis, by specifically inactivating the (β)-catenin gene in the region of Wnt1 expression. To achieve this, mice with a conditional ('floxed') allele of (β)-catenin with required exons flanked by loxP recombination sequences were intercrossed with transgenic mice that expressed Cre recombinase under control of Wnt1 regulatory sequences. (β)-catenin gene deletion resulted in dramatic Brain Malformation and failure of craniofacial development. Absence of part of the midBrain and all of the cerebellum is reminiscent of the conventional Wnt1 knockout (Wnt1(−)(/)(−)), suggesting that Wnt1 acts through (β)-catenin in controlling midBrain-hindBrain development. The craniofacial phenotype, not observed in embryos that lack Wnt1, indicates a role for (β)-catenin in the fate of neural crest cells. Analysis of neural tube explants shows that (β)-catenin is efficiently deleted in migrating neural crest cell precursors. This, together with an increased apoptosis in cells migrating to the cranial ganglia and in areas of prechondrogenic condensations, suggests that removal of (β)-catenin affects neural crest cell survival and/or differentiation. Our results demonstrate the pivotal role of (β)-catenin in morphogenetic processes during Brain and craniofacial development.
-
inactivation of the beta catenin gene by wnt1 cre mediated deletion results in dramatic Brain Malformation and failure of craniofacial development
Development, 2001Co-Authors: Veronique Brault, Robert Moore, Stefanie Kutsch, Makoto Ishibashi, David H Rowitch, Andrew P Mcmahon, Lukas Sommer, Oreda Boussadia, Rolf KemlerAbstract:('bgr;)-Catenin is a central component of both the cadherin-catenin cell adhesion complex and the Wnt signaling pathway. We have investigated the role of (β)-catenin during Brain morphogenesis, by specifically inactivating the (β)-catenin gene in the region of Wnt1 expression. To achieve this, mice with a conditional ('floxed') allele of (β)-catenin with required exons flanked by loxP recombination sequences were intercrossed with transgenic mice that expressed Cre recombinase under control of Wnt1 regulatory sequences. (β)-catenin gene deletion resulted in dramatic Brain Malformation and failure of craniofacial development. Absence of part of the midBrain and all of the cerebellum is reminiscent of the conventional Wnt1 knockout (Wnt1(−)(/)(−)), suggesting that Wnt1 acts through (β)-catenin in controlling midBrain-hindBrain development. The craniofacial phenotype, not observed in embryos that lack Wnt1, indicates a role for (β)-catenin in the fate of neural crest cells. Analysis of neural tube explants shows that (β)-catenin is efficiently deleted in migrating neural crest cell precursors. This, together with an increased apoptosis in cells migrating to the cranial ganglia and in areas of prechondrogenic condensations, suggests that removal of (β)-catenin affects neural crest cell survival and/or differentiation. Our results demonstrate the pivotal role of (β)-catenin in morphogenetic processes during Brain and craniofacial development.