The histone demethylase KDM5 is required for synaptic structure and function at the Drosophila neuromuscular junction

Helen M. Belalcazar, Emily L. Hendricks, Sumaira Zamurrad, Faith L.W. Liebl, Julie Secombe

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Mutations in the genes encoding the lysine demethylase 5 (KDM5) family of histone demethylases are observed in individuals with intellectual disability (ID). Despite clear evidence linking KDM5 function to neurodevelopmental pathways, how this family of proteins impacts transcriptional programs to mediate synaptic structure and activity remains unclear. Using the Drosophila larval neuromuscular junction (NMJ), we show that KDM5 is required presynaptically for neuroanatomical development and synaptic function. The Jumonji C (JmjC) domain-encoded histone demethylase activity of KDM5, which is expected to be diminished by many ID-associated alleles, is required for appropriate synaptic morphology and neurotransmission. The activity of the C5HC2 zinc finger is also required, as an ID-associated mutation in this motif reduces NMJ bouton number, increases bouton size, and alters microtubule dynamics. KDM5 therefore uses demethylase-dependent and independent mechanisms to regulate NMJ structure and activity, highlighting the complex nature by which this chromatin modifier carries out its neuronal gene-regulatory programs. Mutations in the KDM5 family of histone demethylases are observed in individuals with intellectual disability (ID). Belalcazar et al. show that KDM5-regulated transcription is necessary in Drosophila for proper neuroanatomical development and neurotransmission at the glutamatergic larval neuromuscular junction.

Original languageEnglish (US)
Article number108753
JournalCell Reports
Volume34
Issue number7
DOIs
StatePublished - Feb 16 2021

Keywords

  • Drosophila
  • KDM5
  • glutamatergic signaling
  • histone demethylase
  • intellectual disability
  • microtubule dynamics
  • motor neuron
  • neuromuscular junction
  • transcription

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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