Enhancer AAVs for targeting spinal motor neurons and descending motor pathways in rodents and macaque

Author:

Kussick EmilyORCID,Johansen NelsonORCID,Taskin NazORCID,Wynalda BrookeORCID,Martinez RefugioORCID,Groce Erin L.ORCID,Reding MelissaORCID,Liang ElizabethORCID,Shulga LyudmilaORCID,Huang CindyORCID,Casper TamaraORCID,Clark MichaelORCID,Ho WindyORCID,Gao YuanORCID,van Velthoven Cindy T.J.ORCID,Sobieski CassandraORCID,Ferrer RebeccaORCID,Berg Melissa R.ORCID,Curtis Britni C.ORCID,English ChrisORCID,Day Jesse C.ORCID,Fortuna MichalORCID,Donadio NicholasORCID,Newman DakotaORCID,Yao ShenqinORCID,Chakka Anish BhaswanthORCID,Goldy JeffORCID,Torkelson AmyORCID,Guzman Junitta B.ORCID,Chakrabarty RushilORCID,Nguy BeagenORCID,Guilford NathanORCID,Pham Trangthanh H.ORCID,Wright VonnORCID,Ronellenfitch KaraORCID,Gudsnuk KathrynORCID,Thyagarajan BargaviORCID,Smith Kimberly A.ORCID,Dee NickORCID,Zeng HongkuiORCID,Yao ZizhenORCID,Tasic BosiljkaORCID,Levi Boaz P.ORCID,Hodge RebeccaORCID,Bakken Trygve E.ORCID,Lein Ed S.ORCID,Ting Jonathan T.ORCID,Daigle Tanya L.ORCID

Abstract

SummaryExperimental access to cell types within the mammalian spinal cord is severely limited by the availability of genetic tools. To enable access to lower motor neurons (LMNs) and LMN subtypes, which function to integrate information from the brain and control movement through direct innervation of effector muscles, we generated single cell multiome datasets from mouse and macaque spinal cords and discovered putative enhancers for each neuronal population. We cloned these enhancers into adeno-associated viral vectors (AAVs) driving a reporter fluorophore and functionally screened them in mouse. The most promising candidate enhancers were then extensively characterized using imaging and molecular techniques and further tested in rat and macaque to show conservation of LMN labeling. Additionally, we combined enhancer elements into a single vector to achieve simultaneous labeling of upper motor neurons (UMNs) and LMNs. This unprecedented LMN toolkit will enable future investigations of cell type function across species and potential therapeutic interventions for human neurodegenerative diseases.

Publisher

Cold Spring Harbor Laboratory

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