| Autor: |
Martin D. Burkhalter, Tom Stiff, Lars D. Maerz, Teresa Casar Tena, Heike Wiese, Julian Gerhards, Steffen A. Sailer, Linh Anna Trúc Vu, Max Duong Phu, Cornelia Donow, Marius Alupei, Sebastian Iben, Marco Groth, Sebastian Wiese, Joseph A. Church, Penelope A. Jeggo, Melanie Philipp |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Cell Death and Disease, Vol 15, Iss 9, Pp 1-14 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2041-4889 |
| DOI: |
10.1038/s41419-024-07042-5 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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