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Paul A Trainor - One of the best experts on this subject based on the ideXlab platform.
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tp53 dependent and independent signaling underlies the pathogenesis and possible prevention of acrofacial dysostosis cincinnati type
Human Molecular Genetics, 2018Co-Authors: Paul A Trainor, Kristin Noack E Watt, Cynthia L Neben, Shawn M Hall, Amy E MerrillAbstract:Ribosome biogenesis is a global process required for growth and proliferation in all Cells, but disruptions in this process surprisingly lead to tissue-specific phenotypic disorders termed ribosomopathies. Pathogenic variants in the RNA Polymerase (Pol) I subunit POLR1A cause Acrofacial Dysostosis-Cincinnati type, which is characterized by craniofacial and limb anomalies. In a zebrafish model of Acrofacial Dysostosis-Cincinnati type, we demonstrate that polr1a-/- mutants exhibit deficient 47S rRNA transcription, reduced monosomes and polysomes and, consequently, defects in protein translation. This results in Tp53-dependent neuroepithelial apoptosis, diminished Neural Crest Cell proliferation and cranioskeletal anomalies. This indicates that POLR1A is critical for rRNA transcription, which is considered a rate limiting step in ribosome biogenesis, underpinning its requirement for neuroepithelial Cell and Neural Crest Cell proliferation and survival. To understand the contribution of the Tp53 pathway to the pathogenesis of Acrofacial Dysostosis-Cincinnati type, we genetically inhibited tp53 in polr1a-/- mutant embryos. Tp53 inhibition suppresses neuroepithelial apoptosis and partially ameliorates the polr1a mutant phenotype. However, complete rescue of cartilage development is not observed due to the failure to improve rDNA transcription and Neural Crest Cell proliferation. Altogether, these data reveal specific functions for both Tp53-dependent and independent signaling downstream of polr1a in ribosome biogenesis during Neural Crest Cell and craniofacial development, in the pathogenesis of Acrofacial Dysostosis-Cincinnati type. Furthermore, our work sets the stage for identifying Tp53-independent therapies to potentially prevent Acrofacial dysostosis-Cincinnati type and other similar ribosomopathies.
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Schematic summary of elevated Shh signaling resulting in cranial nerve defects.
2015Co-Authors: Hiroshi Kurosaka, Paul A Trainor, Margot Leroux-berger, Angelo IulianellaAbstract:(A) During normal development, Neural Crest Cells migrating from rhombomere 2 (r2) or 4 (r4) interact with placodal Cells to develop the cranial nerves. (B) Ptch1Wig/Wig embryos exhibit excessive Shh signaling leading to a reduction in Neural Crest Cells and survival factors, which results in reduced Neural Crest Cell-placode interactions and cranial nerve patterning defects.
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the developmental etiology and pathogenesis of hirschsprung disease
Translational Research, 2013Co-Authors: Naomi Butler E Tjaden, Paul A TrainorAbstract:The enteric nervous system is the part of the autonomic nervous system that directly controls the gastrointestinal tract. Derived from a multipotent, migratory Cell population called the Neural Crest, a complete enteric nervous system is necessary for proper gut function. Disorders that arise as a consequence of defective Neural Crest Cell development are termed neurocristopathies. One such disorder is Hirschsprung disease (HSCR), also known as congenital megacolon or intestinal aganglionosis. HSCR occurs in 1/5000 live births and typically presents with the inability to pass meconium, along with abdominal distension and discomfort that usually requires surgical resection of the aganglionic bowel. This disorder is characterized by a congenital absence of neurons in a portion of the intestinal tract, usually the distal colon, because of a disruption of normal Neural Crest Cell migration, proliferation, differentiation, survival, and/or apoptosis. The inheritance of HSCR disease is complex, often non-Mendelian, and characterized by variable penetrance. Extensive research has identified a number of key genes that regulate Neural Crest Cell development in the pathogenesis of HSCR including RET , GDNF , GFRα1 , NRTN , EDNRB , ET3 , ZFHX1B , PHOX2b , SOX10 , and SHH . However, mutations in these genes account for only ∼50% of the known cases of HSCR. Thus, other genetic mutations and combinations of genetic mutations and modifiers likely contribute to the etiology and pathogenesis of HSCR. The aims of this review are to summarize the HSCR phenotype, diagnosis, and treatment options; to discuss the major genetic causes and the mechanisms by which they disrupt normal enteric Neural Crest Cell development; and to explore new pathways that may contribute to HSCR pathogenesis.
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tcof1 treacle is required for Neural Crest Cell formation and proliferation deficiencies that cause craniofacial abnormalities
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Jill Dixon, Natalie Carmaline Jones, Lisa L Sandell, Sachintha M Jayasinghe, Jennifer F Crane, Jeanphillipe Rey, Michael J Dixon, Paul A TrainorAbstract:Neural Crest Cells are a migratory Cell population that give rise to the majority of the cartilage, bone, connective tissue, and sensory ganglia in the head. Abnormalities in the formation, proliferation, migration, and differentiation phases of the Neural Crest Cell life cycle can lead to craniofacial malformations, which constitute one-third of all congenital birth defects. Treacher Collins syndrome (TCS) is characterized by hypoplasia of the facial bones, cleft palate, and middle and external ear defects. Although TCS results from autosomal dominant mutations of the gene TCOF1, the mechanistic origins of the abnormalities observed in this condition are unknown, and the function of Treacle, the protein encoded by TCOF1, remains poorly understood. To investigate the developmental basis of TCS we generated a mouse model through germ-line mutation of Tcof1. Haploinsufficiency of Tcof1 leads to a deficiency in migrating Neural Crest Cells, which results in severe craniofacial malformations. We demonstrate that Tcof1/Treacle is required Cell-autonomously for the formation and proliferation of Neural Crest Cells. Tcof1/Treacle regulates proliferation by controlling the production of mature ribosomes. Therefore, Tcof1/Treacle is a unique spatiotemporal regulator of ribosome biogenesis, a deficiency that disrupts Neural Crest Cell formation and proliferation, causing the hypoplasia characteristic of TCS craniofacial anomalies.
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role of morphogens in Neural Crest Cell determination
Journal of Neurobiology, 2005Co-Authors: Natalie Carmaline Jones, Paul A TrainorAbstract:The Neural Crest is a transient, migratory Cell population found in all vertebrate embryos that generate a diverse range of Cell and tissue derivatives including, but not limited, to the neurons and glia of the peripheral nervous system, smooth muscle, connective tissue, melanocytes, craniofacial cartilage, and bone. Over the past few years, many studies have provided tremendous insights into understanding the mechanisms regulating the induction and migration of Neural Crest Cell development. This review highlights the surprising and perhaps unexpected roles for morphogens in these distinct processes. A comparison of studies performed in several different vertebrates emphasizes the requirement for coordination between multiple signaling pathways in the induction and migration of Neural Crest Cells in the developing embryo. © 2005 Wiley Periodicals, Inc. J Neurobiol 64: 388–404, 2005
Rolf Kemler - One of the best experts on this subject based on the ideXlab platform.
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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, Andrew P Mcmahon, David H Rowitch, Robert Moore, Stefanie Kutsch, Makoto Ishibashi, 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.
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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, Andrew P Mcmahon, David H Rowitch, Robert Moore, Stefanie Kutsch, Makoto Ishibashi, 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.
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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, Andrew P Mcmahon, David H Rowitch, Robert Moore, Stefanie Kutsch, Makoto Ishibashi, 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.
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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, Andrew P Mcmahon, David H Rowitch, Robert Moore, Stefanie Kutsch, Makoto Ishibashi, 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.
Veronique Brault - One of the best experts on this subject based on the ideXlab platform.
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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, Andrew P Mcmahon, David H Rowitch, Robert Moore, Stefanie Kutsch, Makoto Ishibashi, 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.
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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, Andrew P Mcmahon, David H Rowitch, Robert Moore, Stefanie Kutsch, Makoto Ishibashi, 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.
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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, Andrew P Mcmahon, David H Rowitch, Robert Moore, Stefanie Kutsch, Makoto Ishibashi, 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.
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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, Andrew P Mcmahon, David H Rowitch, Robert Moore, Stefanie Kutsch, Makoto Ishibashi, 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.
Andrew P Mcmahon - One of the best experts on this subject based on the ideXlab platform.
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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, Andrew P Mcmahon, David H Rowitch, Robert Moore, Stefanie Kutsch, Makoto Ishibashi, 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.
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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, Andrew P Mcmahon, David H Rowitch, Robert Moore, Stefanie Kutsch, Makoto Ishibashi, 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.
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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, Andrew P Mcmahon, David H Rowitch, Robert Moore, Stefanie Kutsch, Makoto Ishibashi, 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.
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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, Andrew P Mcmahon, David H Rowitch, Robert Moore, Stefanie Kutsch, Makoto Ishibashi, 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.
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Analysis of Neural Crest Cell migration in Splotch mice using a Neural Crest-specific LacZ reporter.
Developmental biology, 1997Co-Authors: George N. Serbedzija, Andrew P McmahonAbstract:Abstract Studies on the mouseSplotch(Sp) mutation, a deletion in the transcription factor Pax-3, have revealed that Pax-3 is essential for normal development of the Neural Crest. We have investigated the defect in Neural Crest development using a Wnt-l::LacZ reporter construct to mark Neural Crest Cells. Staining embryos for β-galactosidase activity at different developmental stages revealed a severe reduction in the number of Neural Crest Cells which emigrated from the Neural tube at the vagal and rostral trunk levels. At the caudal thoracic, lumbar, and sacral levels there was a complete loss of Neural Crest Cell emigration. In contrast to previous work in culture, we saw no evidence for any delay in the onset of Neural Crest Cell migration at anterior levels. Pax-3 is expressed in the dorsal Neural tube, where the Neural Crest Cells originate, in migrating Neural Crest Cells, and in somitic Cells along the migratory pathway. Hence, it is not clear which aspect of the Pax-3 expression accounts for the observed phenotype. We addressed this problem by transplanting Neural tissue between mouse and chick embryos. Our studies indicate that the defect in theSplotchmutation is not intrinsic to the Neural Crest Cells themselves, but appears to reflect inappropriate Cell interactions either within the Neural tube or between the Neural tube and the somite.
Lukas Sommer - One of the best experts on this subject based on the ideXlab platform.
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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, Andrew P Mcmahon, David H Rowitch, Robert Moore, Stefanie Kutsch, Makoto Ishibashi, 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.
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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, Andrew P Mcmahon, David H Rowitch, Robert Moore, Stefanie Kutsch, Makoto Ishibashi, 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.
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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, Andrew P Mcmahon, David H Rowitch, Robert Moore, Stefanie Kutsch, Makoto Ishibashi, 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.
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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, Andrew P Mcmahon, David H Rowitch, Robert Moore, Stefanie Kutsch, Makoto Ishibashi, 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.