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Review
. 2024 Jun 26;52(3):1159-1171.
doi: 10.1042/BST20230757.

Retrotransposons in embryogenesis and neurodevelopment

Mary Jo Talley  1 , Michelle S Longworth  1   2
Affiliations
Review

Retrotransposons in embryogenesis and neurodevelopment

Mary Jo Talley et al. Biochem Soc Trans. .

Abstract

Retrotransposable elements (RTEs) are genetic elements that can replicate and insert new copies into different genomic locations. RTEs have long been identified as 'parasitic genes', as their mobilization can cause mutations, DNA damage, and inflammation. Interestingly, high levels of retrotransposon activation are observed in early embryogenesis and neurodevelopment, suggesting that RTEs may possess functional roles during these stages of development. Recent studies demonstrate that RTEs can function as transcriptional regulatory elements through mechanisms such as chromatin organization and noncoding RNAs. It is clear, however, that RTE expression and activity must be restrained at some level during development, since overactivation of RTEs during neurodevelopment is associated with several developmental disorders. Further investigation is needed to understand the importance of RTE expression and activity during neurodevelopment and the balance between RTE-regulated development and RTE-mediated pathogenesis.

Keywords: LINE-1; neurodevelopment; neurodevelopmental disorders; retrotransposon.

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Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

Figures

Figure 1.
Figure 1.. Lifecycle of an active long interspersed nuclear element-1 (LINE-1) element.
(A) Structure of LINE-1. ORF1 encodes an RNA-binding protein that demonstrates nucleic acid chaperone activity while ORF2 encodes a 150 kDa protein that has endonuclease and reverse transcriptase capabilities [124–127]. Expression of both ORF1 and ORF2 is required for retrotransposition [128–131]. ORF0 is a primate-specific antisense reading frame located in the 5'UTR that may play a role in LINE-1 retrotransposition [5]. ORF0 also provides an alternative promoter in the antisense direction that may produce chimeric LINE-1 transcripts that may act as lncRNAs [60]. (B) Mobilization of LINE-1. (1) LINE-1 RNA is expressed and transported out of the nucleus. (2) LINE-1 RNA is translated. (3) ORF1 and ORF2 proteins preferentially bind to their own LINE-1 mRNA to form a ribonucleoprotein and transported back into the nucleus [125,130,132–134]. (4) ORF2 protein cleaves DNA and reverse transcribes LINE-1 back into the genome via target-primed reverse transcription (TPRT) [135–137]. TPRT is a process where a 3′-hydroxyl group that is revealed when ORF2p cleaves the genomic DNA is used as a primer to reverse transcribe LINE-1 mRNA. However, this classic understanding of reverse transcription is being challenged as evidence of reverse transcription has also been observed in the cytoplasm [18,20,111,137].
Figure 2.
Figure 2.. Summary of RTE activity in development.
(A) During early embryogenesis, RTEs are expressed and required for development. Knockdown of MERVL halts development at the 2-cell stage, while depletion of LINE-1 halts development at the 4- to 8-cell stage during mouse embryogenesis [78–84]. Additionally, overexpression of LINE-1 also halts development at the 8- to 16-cell stage [84]. (B) After cleavage ends, different RTEs play different roles in development. In the human blastocyst, most cells within the inner cell mass (ICM) express HERV-H, which inhibits LINE-1 [39]. Cells that express LINE-1 also express DNA damage response markers and apoptotic genes; these cells are called ‘Reject cells' [39]. Reject cells are thought to be part of a ‘quality control' pruning process in the blastocyst [39]. (C) LINE-1 expression has been observed in both developing and aged human brains, where specific LINE-1 loci are differentially expressed [60]. While LINE-1 expression in the brain is supported by several studies, the mobilization rate of LINE-1 is currently disputed. (D) Mechanisms by which LINE-1 expression can impact development. (i) LINE-1 and Alu promote heterochromatin and euchromatin compartmentalization, respectively [87]. (ii) LINE-1 acts as a decoy for PRC2 in depositing repressive histone marks [59]. (iii) LINE-1 insertions can create chimeric proteins. These newly generated proteins may contribute to diversity in the brain (reviewed in [122]).
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