Abnormal centrosome and spindle morphology in a patient with autosomal recessive primary microcephaly type 2 due to compound heterozygous WDR62 gene mutation

Farag, Heba Gamal; Froehler, Sebastian; Oexle, Konrad; Ravindran, Ethiraj; Schindler, Detlev; Staab, Timo; Huebner, Angela; Kraemer, Nadine; Chen, Wei; Kaindl, Angela M.

doi:10.1186/1750-1172-8-178

Cited by 39 publications

(46 citation statements)

References 45 publications

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“…Previous studies on the intracellular distribution of ectopically expressed WDR62 with missense MCPH mutations that altered evolutionarily conserved residues revealed lost or substantially reduced spindle pole accumulation (Nicholas et al, 2010). Similar defects in spindle localization were also reported in primary cells isolated from an MCPH patient (Farag et al, 2013). MCPH-associated WDR62 mutants failed to rescue altered neuroprogenitor cell divisions induced by embryonic WDR62 depletion (Xu et al, 2014).…”

Section: Introductionsupporting

confidence: 56%

Opposing roles for JNK and Aurora A in regulating WD40-Repeat Protein 62 association with spindle microtubules

Lim

Yeap

Zhao

et al. 2014

Journal of Cell Science

101

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BSTRACT WD40-repeat protein 62 (WDR62) is a spindle pole protein required for normal cell division and neuroprogenitor differentiation during brain development. Microcephaly-associated mutations in WDR62 lead to mitotic mislocalization, highlighting a crucial requirement for precise WDR62 spatiotemporal distribution, although the regulatory mechanisms are unknown. Here, we demonstrate that the WD40-repeat region of WDR62 is required for microtubule association, whereas the disordered C-terminal region regulates cell-cycledependent compartmentalization. In agreement with a functional requirement for the WDR62-JNK1 complex during neurogenesis, WDR62 specifically recruits JNK1 (also known as MAPK8), but not JNK2 (also known as MAPK9), to the spindle pole. However, JNKmediated phosphorylation of WDR62 T1053 negatively regulated microtubule association, and loss of JNK signaling resulted in constitutive WDR62 localization to microtubules irrespective of cell cycle stage. In contrast, we identified that Aurora A kinase (AURKA) and WDR62 were in complex and that AURKA-mediated phosphorylation was required for the spindle localization of WDR62 during mitosis. Our studies highlight complex regulation of WDR62 localization, with opposing roles for JNK and AURKA in determining its spindle association.

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Section: Introductionsupporting

confidence: 56%

Opposing roles for JNK and Aurora A in regulating WD40-Repeat Protein 62 association with spindle microtubules

Lim

Yeap

Zhao

et al. 2014

Journal of Cell Science

101

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“…Further experiments revealed an increased cellular proliferation by WDR62 overexpression and centrosome amplification by the concurrent overexpression of WDR62 and TPX2 in lung cancer cells and non‐cancerous bronchial epithelial cells for the first time. WDR62 is localized in the cytoplasm, including the centrosome, and mutant WDR62 causing primary microcephaly induced an abnormal centrosome . Moreover, the expression of both WDR62 and TPX2 led to AURKA activation in not only lung cancer cells in the present study, but also in uterine cervix cancer cells, and AURKA overexpression caused centrosome amplification in previous studies .…”

Section: Discussionsupporting

confidence: 67%

“…The human WDR62 ( WD repeat domain 62 ) gene is localized in the 19q13.12 region and encodes a 1523 amino acid protein that is localized in the cytoplasm and centrosome . WDR62 plays important roles in cell cycle progression, spindle maintenance, and cell proliferation, and germline mutations of the WDR62 gene cause primary microcephaly, which is characterized by a rare neurodevelopmental disease with severe microcephaly at birth . In human malignancies, the overexpression of WDR62 protein has been recently reported in gastric cancer and ovarian cancer; however, whether abnormal WDR62 expression is present in other types of cancers, including LAC, remains unclear.…”

Section: Introductionmentioning

confidence: 99%

WDR62 overexpression is associated with a poor prognosis in patients with lung adenocarcinoma

Shinmura

Kato

Kawanishi

et al. 2017

Molecular Carcinogenesis

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Human WDR62, which is localized in the cytoplasm including the centrosome, is known to be responsible for primary microcephaly; however, the role of WDR62 abnormality in cancers remains largely unknown. In this study, we aimed to reveal the pathological role of WDR62 abnormality in lung adenocarcinoma (LAC). We first examined the WDR62 mRNA expression level of LAC (n = 64) using a QRT-PCR analysis and found that WDR62 mRNA transcripts were significantly overexpressed in LAC (P = 0.0432, Wilcoxon matched pairs test). An immunohistochemical analysis for LAC (n = 237) showed that WDR62 proteins were also significantly overexpressed in LAC (P < 0.0001, Mann-Whitney U test). A Kaplan-Meier analysis demonstrated that patients with LAC who exhibit WDR62 overexpression have a short overall survival (P = 0.0378, log-rank test), and a multivariate analysis revealed that WDR62 overexpression was an independent predictor of a poor survival outcome among LAC patients (hazard ratio, 2.032; 95% confidence interval, 1.071-3.777; P = 0.0305). Next, we examined the functional effect of WDR62 overexpression on the lung cancer cell line H1299. WDR62-overexpressing lung cancer cells exhibited an increase in cell growth. Moreover, the concurrent overexpression of WDR62 and TPX2, a WDR62-interacting protein that is also overexpressed in LAC, induced centrosome amplification in the lung cells. Finally, we disclosed that the concurrent overexpression of WDR62 and TPX2 is common in diverse human cancers, using data from the Cancer Genome Atlas. These results suggested that WDR62 overexpression is associated with a poor prognosis in patients with LAC and leads to an increase in the malignant potential of lung cells.

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“…16,22,37 Analysis of patient-derived lymphocytes from an individual with compound heterozygous mutations that included the c.1313G>A (p.R438H) mutation revealed expression of missense mutant protein with defective mitotic localization. 37 This was consistent with the notion that a spindle localization deficit contributes to WDR62 pathomechanism and highlights the importance of mitotic specific functions in neurodevelopment. In co-immunoprecipitation studies we showed that interactions between AURKA and several MCPH-associated WDR62 mutants were compromised.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, AURKA interaction was not detected in complex with the WDR62 R438H mutant, one of the most commonly reported wdr62 MCPH mutations. 16,37 We extended our analysis to the AURKAdependent Ser49/Thr50 phosphorylation of WDR62 with MCPH-linked mutations. Assessment of the phosphorylation status of WDR62 Ser49/Thr50 using quantitative mass spectrometry revealed a 10.5-fold increase in phosphorylation in M-phase synchronized cells compared to S phase ( Figure 6B).…”

Section: Aurka Does Not Signal To Wdr62 Mcph Mutantsmentioning

confidence: 99%

Aurora A phosphorylation of WD40-repeat protein 62 in mitotic spindle regulation

et al. 2016

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Mitotic spindle organization is regulated by centrosomal kinases that potentiate recruitment of spindleassociated proteins required for normal mitotic progress including the microcephaly protein WD40-repeat protein 62 (WDR62). WDR62 functions underlie normal brain development as autosomal recessive mutations and wdr62 loss cause microcephaly. Here we investigate the signaling interactions between WDR62 and the mitotic kinase Aurora A (AURKA) that has been recently shown to cooperate to control brain size in mice. The spindle recruitment of WDR62 is closely correlated with increased levels of AURKA following mitotic entry. We showed that depletion of TPX2 attenuated WDR62 localization at spindle poles indicating that TPX2 co-activation of AURKA is required to recruit WDR62 to the spindle. We demonstrated that AURKA activity contributed to the mitotic phosphorylation of WDR62 residues Ser49 and Thr50 and phosphorylation of WDR62 N-terminal residues was required for spindle organization and metaphase chromosome alignment. Our analysis of several MCPH-associated WDR62 mutants (V65M, R438H and V1314RfsX18) that are mislocalized in mitosis revealed that their interactions and phosphorylation by AURKA was substantially reduced consistent with the notion that AURKA is a key determinant of WDR62 spindle recruitment. Thus, our study highlights the role of AURKA signaling in the spatiotemporal control of WDR62 at spindle poles where it maintains spindle organization.

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Abnormal centrosome and spindle morphology in a patient with autosomal recessive primary microcephaly type 2 due to compound heterozygous WDR62 gene mutation

Cited by 39 publications

References 45 publications

Opposing roles for JNK and Aurora A in regulating WD40-Repeat Protein 62 association with spindle microtubules

Opposing roles for JNK and Aurora A in regulating WD40-Repeat Protein 62 association with spindle microtubules

WDR62 overexpression is associated with a poor prognosis in patients with lung adenocarcinoma

Aurora A phosphorylation of WD40-repeat protein 62 in mitotic spindle regulation

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