Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy

Martin, Carol-Anne; Ahmad, Ilyas; Klingseisen, Anna; Hussain, Muhammad Sajid; Bicknell, Louise S.; Leitch, Andrea; Nürnberg, Gudrun; Toliat, Mohammad Reza; Murray, Jennie; Hunt, David; Khan, Fawad; Ali, Zafar; Tinschert, Sigrid; Ding, James; Keith, Charlotte; Harley, Margaret E.; Heyn, Patricia; Müller, Rolf; Hoffmann, Ingrid; Cormier‐Daire, Valérie; Dollfus, Hélène; Dupuis, Lucie; Bashamboo, Anu; McElreavey, Kenneth; Kariminejad, Ariana; Mendoza-Londoño, Roberto; Moore, Anthony T.; Saggar, Anand; Schlechter, Catie; Weleber, Richard G.; Thiele, Holger; Altmüller, Janine; Höhne, Wolfgang; Hurles, Matthew E.; Noegel, Angelika A.; Baig, Shahid Mahmood; Nürnberg, Peter; Jackson, Andrew P.

doi:10.1038/ng.3122

Cited by 156 publications

(165 citation statements)

References 49 publications

(64 reference statements)

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“…Mutations in centrosomal proteins cause developmental disorders such as primary microcephaly and Seckel syndrome (Thornton & Woods, 2009; Kalay et al , 2011; McIntyre et al , 2012; Lancaster et al , 2013; Alcantara & O'Driscoll, 2014; Bazzi & Anderson, 2014; Insolera et al , 2014; Martin et al , 2014). Microcephaly is a neurodevelopmental disorder leading to extreme reduction in brain size.…”

Section: Introductionmentioning

confidence: 99%

CPAP promotes timely cilium disassembly to maintain neural progenitor pool

et al. 2016

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A mutation in the centrosomal‐P4.1‐associated protein (CPAP) causes Seckel syndrome with microcephaly, which is suggested to arise from a decline in neural progenitor cells (NPCs) during development. However, mechanisms of NPCs maintenance remain unclear. Here, we report an unexpected role for the cilium in NPCs maintenance and identify CPAP as a negative regulator of ciliary length independent of its role in centrosome biogenesis. At the onset of cilium disassembly, CPAP provides a scaffold for the cilium disassembly complex (CDC), which includes Nde1, Aurora A, and OFD1, recruited to the ciliary base for timely cilium disassembly. In contrast, mutated CPAP fails to localize at the ciliary base associated with inefficient CDC recruitment, long cilia, retarded cilium disassembly, and delayed cell cycle re‐entry leading to premature differentiation of patient iPS‐derived NPCs. Aberrant CDC function also promotes premature differentiation of NPCs in Seckel iPS‐derived organoids. Thus, our results suggest a role for cilia in microcephaly and its involvement during neurogenesis and brain size control.

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Section: Introductionmentioning

confidence: 99%

CPAP promotes timely cilium disassembly to maintain neural progenitor pool

et al. 2016

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“…Few substrates of Plk4 have been described to date, including STIL (Ohta et al, 2014;Dzhindzhev et al, 2014;Kratz et al, 2015;Arquint et al, 2015;Moyer et al, 2015), GCP6 (also known as TUBGCP6) (Bahtz et al, 2012;Martin et al, 2014) and the F-box protein Fbxw5, a component of the SCF ubiquitin ligase (Puklowski et al, 2011). Cep152 and Cep192 collaborate to recruit Plk4 to centrioles (Cizmecioglu et al, 2010;Hatch et al, 2010;Dzhindzhev et al, 2010;Sonnen et al, 2013;Kim et al, 2013) in order to concentrate Plk4 at the centrioles and facilitate subsequent activation.…”

Section: Introductionmentioning

confidence: 99%

Cep78 is a new centriolar protein involved in Plk4-induced centriole overduplication

Brunk

Zhu

Bärenz

et al. 2016

Journal of Cell Science

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Centrioles are core components of centrosomes, the major microtubule-organizing centers of animal cells, and act as basal bodies for cilia formation. Control of centriole number is therefore crucial for genome stability and embryogenesis. Centriole duplication requires the serine/threonine protein kinase Plk4. Here, we identify Cep78 as a human centrosomal protein and a new interaction partner of Plk4. Cep78 is mainly a centriolar protein that localizes to the centriolar wall. Furthermore, we find that Plk4 binds to Cep78 through its N-terminal domain but that Cep78 is not an in vitro Plk4 substrate. Cep78 colocalizes with Plk4 at centrioles and is required for Plk4-induced centriole overduplication. Interestingly, upon depletion of Cep78, newly synthesized Plk4 is not localized to centrosomes. Our results suggest that the interaction between Cep78 and the N-terminal catalytic domain of Plk4 is a new and important element in the centrosome overduplication process.

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“…One important mechanism for controlling Plk4 abundance is based on the ability of Plk4 to dimerize and trans-autophosphorylate, which results in the generation of a phosphodegron for recognition by Skp, Cullin, F-box containing complex coanatining b-TrCP (SCF b-TrCP ), an E3 ligase, and subsequent degradation of Plk4 by the proteasome (Cunha-Ferreira et al, 2013;Cunha-Ferreira et al, 2009;Guderian et al, 2010;Holland et al, 2012;Holland et al, 2010;Klebba et al, 2013;Sillibourne et al, 2010). Other regulatory mechanisms are likely to exist, and a full understanding of Plk4 regulation is important, particularly in view of the frequent deregulation of this kinase in human cancers (Chng et al, 2008;Macmillan et al, 2001;Mason et al, 2014;van de Vijver et al, 2002) and the impact of Plk4 mutations on brain development and body growth (Martin et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

The E3 ubiquitin ligase Mib1 regulates Plk4 and centriole biogenesis

Čajánek

Glatter

Nigg

2015

Journal of Cell Science

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BSTRACTCentrioles function as core components of centrosomes and as basal bodies for the formation of cilia and flagella. Thus, effective control of centriole numbers is essential for embryogenesis, tissue homeostasis and genome stability. In mammalian cells, the centriole duplication cycle is governed by Polo-like kinase 4 (Plk4). Here, we identify the E3 ubiquitin ligase Mind bomb (Mib1) as a new interaction partner of Plk4. We show that Mib1 localizes to centriolar satellites but redistributes to centrioles in response to conditions that induce centriole amplification. The E3 ligase activity of Mib1 triggers ubiquitylation of Plk4 on multiple sites, causing the formation of Lys11-, Lys29-and Lys48-ubiquitin linkages. These modifications control the abundance of Plk4 and its ability to interact with centrosomal proteins, thus counteracting centriole amplification induced by excess Plk4. Collectively, these results identify the interaction between Mib1 and Plk4 as a new and important element in the control of centriole homeostasis.

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Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy

Cited by 156 publications

References 49 publications

CPAP promotes timely cilium disassembly to maintain neural progenitor pool

CPAP promotes timely cilium disassembly to maintain neural progenitor pool

Cep78 is a new centriolar protein involved in Plk4-induced centriole overduplication

The E3 ubiquitin ligase Mib1 regulates Plk4 and centriole biogenesis

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