Dynamic modulation of the motor neuron translatome during developmental synapse elimination

van der Hoorn, D, Lauria, F, Chaytow, H, Faller, KME, Huang, Y-T, Kline, RA, Signoria, I, Morris, K, Wishart, TM ORCID: https://orcid.org/0000-0002-1973-6654, Groen, EJN, Viero, G and Gillingwater, TH, 2025. Dynamic modulation of the motor neuron translatome during developmental synapse elimination. Science Signaling. ISSN 1945-0877 (Forthcoming)

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Abstract

The developmental sculpting of neuromuscular circuitry in early postnatal life occurs through the process of synapse elimination: supernumerary axon inputs are gradually eliminated from the neuromuscular junction (NMJ) resulting in each muscle fibre being innervated by a single axon terminal. Here, we investigated the molecular pathways underlying this process using a ChAT-RiboTag mouse model in which we isolated ribosome-bound mRNAs in motor neurons over the period of synapse elimination in vivo. Analysis of these mRNAs using translating ribosome affinity purification followed by RNA sequencing (TRAP-seq) revealed dynamic changes in the motor neuron translatome over the first two weeks of life, largely independent of parallel transcriptional changes and correlated with the progressive elimination of supernumerary inputs. Bioinformatic analysis identified distinct clusters of transcripts with discrete temporal translation profiles. Putative pharmacological targeting of the transcript cluster associated with metabolism and the citric acid cycle using two independent small molecules increased the rate of synapse elimination in vivo. Taken together, these data provide a cell-type-specific overview of temporal modifications occurring in the motor neuron translatome during synapse elimination, revealing rapid and dynamic responses to postnatal developmental cues.

Item Type:	Journal article
Publication Title:	Science Signaling
Creators:	van der Hoorn, D., Lauria, F., Chaytow, H., Faller, K.M.E., Huang, Y.-T., Kline, R.A., Signoria, I., Morris, K., Wishart, T.M., Groen, E.J.N., Viero, G. and Gillingwater, T.H.
Publisher:	American Association for the Advancement of Science
Date:	25 February 2025
ISSN:	1945-0877
Identifiers:	Number Type 2387998 Other
Divisions:	Schools > School of Science and Technology
Record created by:	Jeremy Silvester
Date Added:	28 Feb 2025 10:18
Last Modified:	28 Feb 2025 10:18
URI:	https://irep.ntu.ac.uk/id/eprint/53147

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