The CES-2-related transcription factor E4BP4 is an intrinsic regulator of motoneuron growth and survival

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Abstract
The regulation of neuronal growth and survival during development requires interplay between extrinsic and intrinsic factors. Among the latter,transcription factors play a key role. In the nematode, the transcription factor CES-2 predisposes neurosecretory motoneurons to death, whereas E4BP4(NFIL3), one of its vertebrate homologs, regulates survival of pro-B lymphocytes. We show that E4BP4 is expressed by embryonic rat and chicken motoneurons in vivo, with levels being highest in neurons that survive the period of naturally occurring cell death. Overexpression of E4BP4 by electroporation of purified motoneurons in culture protected them almost completely against cell death triggered by removal of neurotrophic factors or activation of death receptors. Moreover, E4BP4 strongly enhanced neuronal cell size and axonal growth. Axons of motoneurons transfected with E4BP4 were 3.5-fold longer than control neurons grown on laminin; this effect required the activity of PI3 kinase. In vivo, overexpression of E4BP4 in chicken embryos reduced the number of dying motoneurons by 45%. Our results define E4BP4 as a novel intrinsic regulator of motoneuron growth and survival. Pathways regulated by E4BP4 are of potential interest both for understanding neuromuscular development and for promoting neuronal survival and regeneration in pathological situations.