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.
Highlights
ATF2 belongs to the leucine-zipper domain-containing CREB/ ATF transcription factor family
To produce a neuronal cell-specific ATF2 deletion, we crossed nestin-Cre mice with mice expressing a floxed allele of Atf2 (Atf2f/f, see Materials and Methods)
The crosses led to the effective deletion of the DNA binding domain of ATF2 as normal ATF2 protein was no longer detected in E18.5 brain of Atf2f/f;nestin-Cre mice (Atf2Dneuron) (Figure S1A)
Summary
ATF2 belongs to the leucine-zipper domain-containing CREB/ ATF transcription factor family. It binds DNA as a homodimer on calcium/cAMP response element (CRE) sequences or as a heterodimer with structurally related AP-1 proteins, such as cJun, to control the expression of a variety of target genes [1]. ATF2 is a substrate for MAP kinases, including c-Jun N-terminal kinase (JNK), p38 kinase and p44/p42 MAPK (ERK1/2) [2,3,4]. MAPK phosphorylation of two threonine (Thr) residues, Thr and Thr, is required for transcriptional activation of ATF2 [4,5]. ATF2 has been shown to be phosphorylated by ATM kinase in response to DNA damage [10]
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