Expanded tRNA methyltransferase family member TRMT9B regulates synaptic growth and function

Author:

Hogan Caley A1ORCID,Gratz Scott J2ORCID,Dumouchel Jennifer L3ORCID,Thakur Rajan S2ORCID,Delgado Ambar2ORCID,Lentini Jenna M4ORCID,Madhwani Kimberly R5ORCID,Fu Dragony4ORCID,O'Connor‐Giles Kate M26ORCID

Affiliation:

1. Genetics Training Program University of Wisconsin‐Madison Madison WI USA

2. Department of Neuroscience Brown University Providence RI USA

3. Therapeutic Sciences Graduate Program Brown University Providence RI USA

4. Department of Biology, Center for RNA Biology University of Rochester Rochester NY USA

5. Neuroscience Graduate Training Program Brown University Providence RI USA

6. Carney Institute for Brain Science Providence RI USA

Abstract

AbstractNervous system function rests on the formation of functional synapses between neurons. We have identified TRMT9B as a new regulator of synapse formation and function in Drosophila. TRMT9B has been studied for its role as a tumor suppressor and is one of two metazoan homologs of yeast tRNA methyltransferase 9 (Trm9), which methylates tRNA wobble uridines. Whereas Trm9 homolog ALKBH8 is ubiquitously expressed, TRMT9B is enriched in the nervous system. However, in the absence of animal models, TRMT9B's role in the nervous system has remained unstudied. Here, we generate null alleles of TRMT9B and find it acts postsynaptically to regulate synaptogenesis and promote neurotransmission. Through liquid chromatography‐mass spectrometry, we find that ALKBH8 catalyzes canonical tRNA wobble uridine methylation, raising the question of whether TRMT9B is a methyltransferase. Structural modeling studies suggest TRMT9B retains methyltransferase function and, in vivo, disruption of key methyltransferase residues blocks TRMT9B's ability to rescue synaptic overgrowth, but not neurotransmitter release. These findings reveal distinct roles for TRMT9B in the nervous system and highlight the significance of tRNA methyltransferase family diversification in metazoans.

Funder

National Institute of General Medical Sciences

National Institute of Neurological Disorders and Stroke

National Science Foundation

Publisher

Springer Science and Business Media LLC

Subject

Genetics,Molecular Biology,Biochemistry

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