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

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 m...

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Autores principales: Belalcazar, Helen M., Hendricks, Emily L., Zamurrad, Sumaira, Liebl, Faith L.W., Secombe, Julie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945993/
https://www.ncbi.nlm.nih.gov/pubmed/33596422
http://dx.doi.org/10.1016/j.celrep.2021.108753
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author Belalcazar, Helen M.
Hendricks, Emily L.
Zamurrad, Sumaira
Liebl, Faith L.W.
Secombe, Julie
author_facet Belalcazar, Helen M.
Hendricks, Emily L.
Zamurrad, Sumaira
Liebl, Faith L.W.
Secombe, Julie
author_sort Belalcazar, Helen M.
collection PubMed
description 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.
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spelling pubmed-79459932021-03-10 The histone demethylase KDM5 is required for synaptic structure and function at the Drosophila neuromuscular junction Belalcazar, Helen M. Hendricks, Emily L. Zamurrad, Sumaira Liebl, Faith L.W. Secombe, Julie Cell Rep Article 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. 2021-02-16 /pmc/articles/PMC7945993/ /pubmed/33596422 http://dx.doi.org/10.1016/j.celrep.2021.108753 Text en This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Belalcazar, Helen M.
Hendricks, Emily L.
Zamurrad, Sumaira
Liebl, Faith L.W.
Secombe, Julie
The histone demethylase KDM5 is required for synaptic structure and function at the Drosophila neuromuscular junction
title The histone demethylase KDM5 is required for synaptic structure and function at the Drosophila neuromuscular junction
title_full The histone demethylase KDM5 is required for synaptic structure and function at the Drosophila neuromuscular junction
title_fullStr The histone demethylase KDM5 is required for synaptic structure and function at the Drosophila neuromuscular junction
title_full_unstemmed The histone demethylase KDM5 is required for synaptic structure and function at the Drosophila neuromuscular junction
title_short The histone demethylase KDM5 is required for synaptic structure and function at the Drosophila neuromuscular junction
title_sort histone demethylase kdm5 is required for synaptic structure and function at the drosophila neuromuscular junction
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945993/
https://www.ncbi.nlm.nih.gov/pubmed/33596422
http://dx.doi.org/10.1016/j.celrep.2021.108753
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