Nova proteins direct synaptic integration of somatostatin interneurons through activity-dependent alternative splicing

Leena Ali Ibrahim*, Brie Wamsley, Norah Alghamdi, Nusrath Yusuf, Elaine Sevier, Ariel Hairston, Mia Sherer, Xavier Hubert Jaglin, Qing Xu, Lihua Guo, Alireza Khodadadi-Jamayran, Emilia Favuzzi, Yuan Yuan, Jordane Dimidschstein, Robert B. Darnell, Gordon Fishell*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Somatostatin interneurons are the earliest born population of cortical inhibitory cells. They are crucial to support normal brain development and function; however, the mechanisms underlying their integration into nascent cortical circuitry are not well understood. In this study, we begin by demonstrating that the maturation of somatostatin interneurons in mouse somatosensory cortex is activity dependent. We then investigated the relationship between activity, alternative splicing, and synapse formation within this population. Specifically, we discovered that the Nova family of RNA-binding proteins are activity-dependent and are essential for the maturation of soma-tostatin interneurons, as well as their afferent and efferent connectivity. Within this population, Nova2 preferentially mediates the alternative splicing of genes required for axonal formation and synaptic function independently from its effect on gene expression. Hence, our work demonstrates that the Nova family of proteins through alternative splicing are centrally involved in coupling developmental neuronal activity to cortical circuit formation.

Original languageEnglish (US)
Article numbere86842
JournaleLife
Volume12
DOIs
StatePublished - Jun 2023

Bibliographical note

Funding Information:
We would like to thank the NYULMC Division of Advanced Research Technologies and their personnel: Mouse Genotyping Core (Jiali Deng and Jisen Dai); Cytometry and Cell Sorting Core (Kamilah Ryan, Keith Kobylarz, Yulia Chupalova, and Michael Gregory); Genome Technology Center (Adriana Heguy); and Applied Bioinformatics Laboratory (Aristotelis Tsirigos), which is supported in part by grant UL1 TR00038 from the National Center for Advancing Translational Sciences (NCATS), NIH. CCSC and GTC are supported by the Cancer Center Support Grant, P30CA016087, at the Laura and Isaac Perl-mutter Cancer Center. We would also like to thank Yanjie Qiu and Marian Fernandez-Otero for helping with genotyping at Harvard Medical School. We would like to thank the extended Fishell Laboratory for critical reading of the manuscript. Work in the GF lab is supported by the following NIH grants: R01 NS081297, R01 MH071679, UG3 MH120096, P01 NS074972 and by the Simons Foundation SFARI.

Publisher Copyright:
© Ibrahim, Wamsley et al.

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology

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