title: Loss of ATF2 function leads to cranial motoneuron degeneration during embryonic mouse development.
abstract: The 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.
authors.affiliation: Cell Regulation Department, Paterson Institute for Cancer Research, University of Manchester, Manchester, United Kingdom.
authors.forename: Julien
authors.initials: J
authors.lastname: Ackermann
authors.forename: Garry
authors.initials: G
authors.lastname: Ashton
authors.forename: Steve
authors.initials: S
authors.lastname: Lyons
authors.forename: Dominic
authors.initials: D
authors.lastname: James
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Hornung
authors.forename: Nic
authors.initials: N
authors.lastname: Jones
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Breitwieser
mesh_terms: D051698:Activating Transcription Factor 2 / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001369:Axons; D001933:Brain Stem / Q000166:cytology / Q000196:embryology; D054637:Dual-Specificity Phosphatases / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D051379:Mice; D009046:Motor Neurons / Q000473:pathology*; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D012886:Skull / Q000294:innervation*
chemical_list: D051698:Activating Transcription Factor 2; C497106:Atf2 protein, mouse; D016755:Proto-Oncogene Proteins c-jun; D054637:Dual-Specificity Phosphatases