Deciphering the roles of subcellular distribution and interactions involving the MEF2 binding region, the ankyrin repeat binding motif and the catalytic site of HDAC4 in Drosophila neuronal morphogenesis

Tan WJ; Hawley HR; Wilson SJ; Fitzsimons HL

Deciphering the roles of subcellular distribution and interactions involving the MEF2 binding region, the ankyrin repeat binding motif and the catalytic site of HDAC4 in Drosophila neuronal morphogenesis

dc.citation.issue	1
dc.citation.volume	22
dc.contributor.author	Tan WJ
dc.contributor.author	Hawley HR
dc.contributor.author	Wilson SJ
dc.contributor.author	Fitzsimons HL
dc.coverage.spatial	England
dc.date.accessioned	2024-06-26T01:29:52Z
dc.date.available	2024-06-26T01:29:52Z
dc.date.issued	2024-12
dc.description.abstract	BACKGROUND: Dysregulation of nucleocytoplasmic shuttling of histone deacetylase 4 (HDAC4) is associated with several neurodevelopmental and neurodegenerative disorders. Consequently, understanding the roles of nuclear and cytoplasmic HDAC4 along with the mechanisms that regulate nuclear entry and exit is an area of concerted effort. Efficient nuclear entry is dependent on binding of the transcription factor MEF2, as mutations in the MEF2 binding region result in cytoplasmic accumulation of HDAC4. It is well established that nuclear exit and cytoplasmic retention are dependent on 14-3-3-binding, and mutations that affect binding are widely used to induce nuclear accumulation of HDAC4. While regulation of HDAC4 shuttling is clearly important, there is a gap in understanding of how the nuclear and cytoplasmic distribution of HDAC4 impacts its function. Furthermore, it is unclear whether other features of the protein including the catalytic site, the MEF2-binding region and/or the ankyrin repeat binding motif influence the distribution and/or activity of HDAC4 in neurons. Since HDAC4 functions are conserved in Drosophila, and increased nuclear accumulation of HDAC4 also results in impaired neurodevelopment, we used Drosophila as a genetic model for investigation of HDAC4 function. RESULTS: Here we have generated a series of mutants for functional dissection of HDAC4 via in-depth examination of the resulting subcellular distribution and nuclear aggregation, and correlate these with developmental phenotypes resulting from their expression in well-established models of neuronal morphogenesis of the Drosophila mushroom body and eye. We found that in the mushroom body, forced sequestration of HDAC4 in the nucleus or the cytoplasm resulted in defects in axon morphogenesis. The actions of HDAC4 that resulted in impaired development were dependent on the MEF2 binding region, modulated by the ankyrin repeat binding motif, and largely independent of an intact catalytic site. In contrast, disruption to eye development was largely independent of MEF2 binding but mutation of the catalytic site significantly reduced the phenotype, indicating that HDAC4 acts in a neuronal-subtype-specific manner. CONCLUSIONS: We found that the impairments to mushroom body and eye development resulting from nuclear accumulation of HDAC4 were exacerbated by mutation of the ankyrin repeat binding motif, whereas there was a differing requirement for the MEF2 binding site and an intact catalytic site. It will be of importance to determine the binding partners of HDAC4 in nuclear aggregates and in the cytoplasm of these tissues to further understand its mechanisms of action.
dc.description.confidential	false
dc.edition.edition	December 2024
dc.format.pagination	2-
dc.identifier.author-url	https://www.ncbi.nlm.nih.gov/pubmed/38167120
dc.identifier.citation	Tan WJ, Hawley HR, Wilson SJ, Fitzsimons HL. (2024). Deciphering the roles of subcellular distribution and interactions involving the MEF2 binding region, the ankyrin repeat binding motif and the catalytic site of HDAC4 in Drosophila neuronal morphogenesis.. BMC Biol. 22. 1. (pp. 2-).
dc.identifier.doi	10.1186/s12915-023-01800-1
dc.identifier.eissn	1741-7007
dc.identifier.elements-type	journal-article
dc.identifier.issn	1741-7007
dc.identifier.number	2
dc.identifier.pii	10.1186/s12915-023-01800-1
dc.identifier.uri	https://mro.massey.ac.nz/handle/10179/70012
dc.language	eng
dc.publisher	BioMed Central Ltd
dc.publisher.uri	https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-023-01800-1
dc.relation.isPartOf	BMC Biol
dc.rights	(c) The author/s	en
dc.rights.license	CC BY	en
dc.rights.uri	https://creativecommons.org/licenses/by/4.0/	en
dc.subject	Ankyrin repeats
dc.subject	Brain
dc.subject	Drosophila
dc.subject	Eye
dc.subject	HDAC4
dc.subject	Histone deacetylase
dc.subject	MEF2
dc.subject	Mushroom body
dc.subject	Neuron
dc.subject	Photoreceptor
dc.subject	Animals
dc.subject	Ankyrin Repeat
dc.subject	Catalytic Domain
dc.subject	Cell Nucleus
dc.subject	Drosophila
dc.subject	Histone Deacetylases
dc.subject	MEF2 Transcription Factors
dc.subject	Morphogenesis
dc.subject	Neurons
dc.title	Deciphering the roles of subcellular distribution and interactions involving the MEF2 binding region, the ankyrin repeat binding motif and the catalytic site of HDAC4 in Drosophila neuronal morphogenesis
dc.type	Journal article
pubs.elements-id	485434
pubs.organisational-group	Other