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dc.contributor.authorAckermann, Julien
dc.contributor.authorAshton, Garry
dc.contributor.authorLyons, Steve
dc.contributor.authorJames, Dominic I
dc.contributor.authorHornung, J-P
dc.contributor.authorJones, Nic
dc.contributor.authorBreitwieser, Wolfgang
dc.date.accessioned2012-01-09T23:38:30Z
dc.date.available2012-01-09T23:38:30Z
dc.date.issued2011
dc.identifier.citationLoss of ATF2 function leads to cranial motoneuron degeneration during embryonic mouse development. 2011, 6 (4):e19090 PLoS ONEen
dc.identifier.issn1932-6203
dc.identifier.pmid21533046
dc.identifier.doi10.1371/journal.pone.0019090
dc.identifier.urihttp://hdl.handle.net/10541/201133
dc.description.abstractThe AP-1 family transcription factor ATF2 is essential for development and tissue maintenance in mammals. In particular, ATF2 is highly expressed and activated in the brain and previous studies using mouse knockouts have confirmed its requirement in the cerebellum as well as in vestibular sense organs. Here we present the analysis of the requirement for ATF2 in CNS development in mouse embryos, specifically in the brainstem. We discovered that neuron-specific inactivation of ATF2 leads to significant loss of motoneurons of the hypoglossal, abducens and facial nuclei. While the generation of ATF2 mutant motoneurons appears normal during early development, they undergo caspase-dependent and independent cell death during later embryonic and foetal stages. The loss of these motoneurons correlates with increased levels of stress activated MAP kinases, JNK and p38, as well as aberrant accumulation of phosphorylated neurofilament proteins, NF-H and NF-M, known substrates for these kinases. This, together with other neuropathological phenotypes, including aberrant vacuolisation and lipid accumulation, indicates that deficiency in ATF2 leads to neurodegeneration of subsets of somatic and visceral motoneurons of the brainstem. It also confirms that ATF2 has a critical role in limiting the activities of stress kinases JNK and p38 which are potent inducers of cell death in the CNS.
dc.language.isoenen
dc.subject.meshActivating Transcription Factor 2
dc.subject.meshAnimals
dc.subject.meshAxons
dc.subject.meshBrain Stem
dc.subject.meshDual-Specificity Phosphatases
dc.subject.meshEmbryo, Mammalian
dc.subject.meshGene Expression Regulation, Developmental
dc.subject.meshGene Expression Regulation, Enzymologic
dc.subject.meshMice
dc.subject.meshMotor Neurons
dc.subject.meshPhosphorylation
dc.subject.meshProto-Oncogene Proteins c-jun
dc.subject.meshSkull
dc.titleLoss of ATF2 function leads to cranial motoneuron degeneration during embryonic mouse development.en
dc.typeArticleen
dc.contributor.departmentCell Regulation Department, Paterson Institute for Cancer Research, University of Manchester, Manchester, United Kingdom.en
dc.identifier.journalPloS Oneen
html.description.abstractThe AP-1 family transcription factor ATF2 is essential for development and tissue maintenance in mammals. In particular, ATF2 is highly expressed and activated in the brain and previous studies using mouse knockouts have confirmed its requirement in the cerebellum as well as in vestibular sense organs. Here we present the analysis of the requirement for ATF2 in CNS development in mouse embryos, specifically in the brainstem. We discovered that neuron-specific inactivation of ATF2 leads to significant loss of motoneurons of the hypoglossal, abducens and facial nuclei. While the generation of ATF2 mutant motoneurons appears normal during early development, they undergo caspase-dependent and independent cell death during later embryonic and foetal stages. The loss of these motoneurons correlates with increased levels of stress activated MAP kinases, JNK and p38, as well as aberrant accumulation of phosphorylated neurofilament proteins, NF-H and NF-M, known substrates for these kinases. This, together with other neuropathological phenotypes, including aberrant vacuolisation and lipid accumulation, indicates that deficiency in ATF2 leads to neurodegeneration of subsets of somatic and visceral motoneurons of the brainstem. It also confirms that ATF2 has a critical role in limiting the activities of stress kinases JNK and p38 which are potent inducers of cell death in the CNS.


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