The THO Complex Coordinates Transcripts for Synapse Development and Dopamine Neuron Survival

Celine I. Maeder, Jae Ick Kim, Xing Liang, Konstantin Kaganovsky, Ao Shen, Qin Li, Zhaoyu Li, Sui Wang, X. Z.Shawn Xu, Jin Billy Li, Yang Kevin Xiang, Jun B. Ding, Kang Shen

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3 Scopus citations

Abstract

Synaptic vesicle and active zone proteins are required for synaptogenesis. The molecular mechanisms for coordinated synthesis of these proteins are not understood. Using forward genetic screens, we identified the conserved THO nuclear export complex (THOC) as an important regulator of presynapse development in C. elegans dopaminergic neurons. In THOC mutants, synaptic messenger RNAs are retained in the nucleus, resulting in dramatic decrease of synaptic protein expression, near complete loss of synapses, and compromised dopamine function. CRE binding protein (CREB) interacts with THOC to mark synaptic transcripts for efficient nuclear export. Deletion of Thoc5, a THOC subunit, in mouse dopaminergic neurons causes severe defects in synapse maintenance and subsequent neuronal death in the substantia nigra compacta. These cellular defects lead to abrogated dopamine release, ataxia, and animal death. Together, our results argue that nuclear export mechanisms can select specific mRNAs and be a rate-limiting step for neuronal differentiation and survival. The conserved THO complex plays a critical role in neuronal function by regulating the nuclear export of presynaptic transcripts that are specified by the activity-dependent transcription factor CREB.

Original languageEnglish (US)
Pages (from-to)1436-1449.e20
JournalCell
Volume174
Issue number6
DOIs
StatePublished - Sep 6 2018

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Keywords

  • coordinated genetic program
  • CREB
  • dopamine neurons
  • neurodegeneration
  • nuclear export
  • presynapse assembly
  • THO complex

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Maeder, C. I., Kim, J. I., Liang, X., Kaganovsky, K., Shen, A., Li, Q., Li, Z., Wang, S., Xu, X. Z. S., Li, J. B., Xiang, Y. K., Ding, J. B., & Shen, K. (2018). The THO Complex Coordinates Transcripts for Synapse Development and Dopamine Neuron Survival. Cell, 174(6), 1436-1449.e20. https://doi.org/10.1016/j.cell.2018.07.046