LINE-1 retrotransposons contribute to mouse PV interneuron development.

Retrotransposons are mobile DNA sequences duplicated via transcription and reverse transcription of an RNA intermediate. Cis-regulatory elements encoded by retrotransposons can also promote the transcription of adjacent genes. Somatic LINE-1 (L1) retrotransposon insertions have been detected in mammalian neurons. It is, however, unclear whether L1 sequences are mobile in only some neuronal lineages or therein promote neurodevelopmental gene expression. Here we report programmed L1 activation by SOX6, a transcription factor critical for parvalbumin (PV) interneuron development. Mouse PV interneurons permit L1 mobilization in vitro and in vivo, harbor unmethylated L1 promoters and express full-length L1 mRNAs and proteins. Using nanopore long-read sequencing, we identify unmethylated L1s proximal to PV interneuron genes, including a novel L1 promoter-driven Caps2 transcript isoform that enhances neuron morphological complexity in vitro. These data highlight the contribution made by L1 cis-regulatory elements to PV interneuron development and transcriptome diversity, uncovered due to L1 mobility in this milieu.

Description

Acknowledgements: We thank J. D. Boeke, J. L. Garcia-Perez, H. H. Kazazian and J. V. Moran for sharing L1SM, LRE3, L1spa and L1.3 plasmids. We thank W. An, P. Sah, R. Lister, R. Sullivan, S. van de Wakker, A. Gaudin, S. W. Cheetham and members of the Faulkner laboratory for helpful discussions. We acknowledge the QBI and TRI Flow Cytometry suites for technical advice, the Garvan Sequencing Platform and the Australian Genome Research Facility for long-read sequencing, the UQ School of Biomedical Sciences Viral Vector Core for Cre lentivirus synthesis and the QBI Advanced Microscopy Facility for technical assistance and equipment, supported by ARC LIEF grant LE130100078. This work was supported by NHMRC-ARC Dementia Research Development Fellowship GNT1108258 and DFG fellowship BO4460/1-1 (G.O.B.), Australian Government Research Training Program (RTP) Scholarships (J.M.B., M.E.F. and J.d.l.R.B.), NHMRC Investigator Grants GNT1176574 (N.J.), GNT1173476 (S.R.R.) and GNT1173711 (G.J.F.), ARC Discovery Project DP200102919 (S.R.R. and G.J.F.), NHMRC Project Grants GNT1106206 (G.J.F., A.J.H. and L.M.P.) and GNT1126393 (G.J.F.), a CSL Centenary Fellowship (G.J.F.), Andalusian Government EMERGIA20_00225 and Spanish National Research Agency RYC2021_031920-I grants (F.J.S.-L.) and the Mater Foundation. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Funder: Mater Foundation

Funder: Department of Education and Training; doi: https://doi.org/10.13039/501100007912

Funder: Andalusian Government EMERGIA20_00225

Keywords

Animals, Interneurons, Mice, Long Interspersed Nucleotide Elements, Parvalbumins, Retroelements, Male, Neurogenesis, Mice, Inbred C57BL, Gene Expression Regulation, Developmental

Journal Title

Nat Neurosci

Journal ISSN

1097-6256
1546-1726

Volume Title

27

Publisher

Springer Science and Business Media LLC

Publisher DOI

https://doi.org/10.1038/s41593-024-01650-2

Rights

Attribution 4.0 International

Sponsorship

Department of Health | National Health and Medical Research Council (NHMRC) (GNT1173711, GNT1106206, GNT1126393, GNT1108258, GNT1176574, GNT1106206, GNT1173476, GNT1106206)
Department of Education and Training | Australian Research Council (ARC) (DP200102919, DP200102919)
CSL Behring (Centenary Fellowship)
Deutsche Forschungsgemeinschaft (German Research Foundation) (BO4460/1-1)

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