PUBLICATION

Cilia defects upon loss of WDR4 are linked to proteasomal hyperactivity and ubiquitin shortage

Authors
Burkhalter, M.D., Stiff, T., Maerz, L.D., Casar Tena, T., Wiese, H., Gerhards, J., Sailer, S.A., Vu, L.A.T., Duong Phu, M., Donow, C., Alupei, M., Iben, S., Groth, M., Wiese, S., Church, J.A., Jeggo, P.A., Philipp, M.
ID
ZDB-PUB-240910-6
Date
2024
Source
Cell Death & Disease   15: 660660 (Journal)
Registered Authors
Burkhalter, Martin, Duong Phu, Max, Philipp, Melanie, Sailer, Steffen, Vu, Anna
Keywords
none
MeSH Terms
  • Proteasome Endopeptidase Complex*/metabolism
  • Microcephaly/genetics
  • Microcephaly/metabolism
  • Microcephaly/pathology
  • Animals
  • Zebrafish*
  • Fibroblasts/metabolism
  • Humans
  • Ubiquitin*/metabolism
  • Cilia*/metabolism
  • Cilia*/pathology
  • Neurogenesis
(all 12)
PubMed
39251572 Full text @ Cell Death Dis.
Abstract
The WD repeat-containing protein 4 (WDR4) has repeatedly been associated with primary microcephaly, a condition of impaired brain and skull growth. Often, faulty centrosomes cause microcephaly, yet aberrant cilia may also be involved. Here, we show using a combination of approaches in human fibroblasts, zebrafish embryos and patient-derived cells that WDR4 facilitates cilium formation. Molecularly, we associated WDR4 loss-of-function with increased protein synthesis and concomitant upregulation of proteasomal activity, while ubiquitin precursor pools are reduced. Inhibition of proteasomal activity as well as supplementation with free ubiquitin restored normal ciliogenesis. Proteasome inhibition ameliorated microcephaly phenotypes. Thus, we propose that WDR4 loss-of-function impairs head growth and neurogenesis via aberrant cilia formation, initially caused by disturbed protein and ubiquitin homeostasis.
Genes / Markers
Marker Marker Type Name
gapdhGENEglyceraldehyde-3-phosphate dehydrogenase
gli1GENEGLI family zinc finger 1
insGENEpreproinsulin
myl7GENEmyosin, light chain 7, regulatory
nkx2.2aGENENK2 homeobox 2a
wdr4GENEWD repeat domain 4
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Figures
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Expression
No data available
Phenotype
No data available
Mutations / Transgenics
No data available
Human Disease / Model
No data available
Sequence Targeting Reagents
Target Reagent Reagent Type
wdr4MO1-wdr4MRPHLNO
wdr4MO2-wdr4MRPHLNO
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Fish
No data available
Antibodies
Orthology
No data available
Engineered Foreign Genes
No data available
Mapping
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Citation
Burkhalter, M.D., Stiff, T., Maerz, L.D., Casar Tena, T., Wiese, H., Gerhards, J., Sailer, S.A., Vu, L.A.T., Duong Phu, M., Donow, C., Alupei, M., Iben, S., Groth, M., Wiese, S., Church, J.A., Jeggo, P.A., Philipp, M. (2024) Cilia defects upon loss of WDR4 are linked to proteasomal hyperactivity and ubiquitin shortage. Cell Death & Disease. 15:660660.