Abstract
Over the past decade, major discoveries in retrotransposon biology have depicted the neural genome as a dynamic structure during life. In particular, the retrotransposon LINE-1 (L1) has been shown to be transcribed and mobilized in the brain. Retrotransposition in the developing brain, as well as during adult neurogenesis, provides a milieu in which neural diversity can arise. Dysregulation of retrotransposon activity may also contribute to neurological disease. Here, we review recent reports of retrotransposon activity in the brain, and discuss the temporal nature of retrotransposition and its regulation in neural cells in response to stimuli. We also put forward hypotheses regarding the significance of retrotransposons for brain development and neurological function, and consider the potential implications of this phenomenon for neuropsychiatric and neurodegenerative conditions.
Highlights
The mammalian brain is remarkably complex in form and function
If we accept that endogenous L1 mobilization can occur during adult neurogenesis, can it occur in postmitotic neurons? This is a fundamental question because the lifespan of mature neurons can be as long as a human lifespan, and any potential for somatic retrotransposition in this context may lead to the largest absolute accumulation of new L1 insertions found in the brain
It is plausible that, if retrotransposons did contribute to normal brain function, it would be via altered splicing and DNA methylation of genes, with these being routes to perturb the transcriptional output of cells
Summary
The mammalian brain is remarkably complex in form and function. Neural cell diversity underpins this complexity, and has classically been defined in terms of the morphological differences between cell types, their diverse connectivity patterns, physiological and functional properties and the expression of various transcription factors (TFs), cell surface and secreted molecules [1,2]. Recent advances in DNA sequencing and genetic analysis, as well as bioinformatics, have made it possible to identify mutations generating distinct genotypes among the neurons of an individual human brain. These mutations include single-nucleotide variants, copy number variants (CNVs) and retrotransposon insertions [4,5,6,7,8,9,10]. To provide a comprehensive understanding of the roles retrotransposons play in neural function, and their potential contribution to disease, we will first present an overview of the active retrotransposon families in humans, their mobilization mechanism, and experimental strategies for studying neuronal retrotransposition
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