MEKK3 coordinates with FBW7 to regulate WDR62 stability and neurogenesis

Xu, Dan; Yao, Maojin; Wang, Yaqing; Yuan, Ling; Hoeck, Joerg D.; Yu, Jingwen; Liu, Liang; Yeap, Yvonne Y C; Zhang, Weiya; Zhang, Feng; Feng, Yinghang; Ma, Tiantian; Wang, Yujie; Ng, Dominic C. H.; Niu, Xiaoyin; Su, Bing; Behrens, Axel; Xu, Zhiheng

doi:10.1371/journal.pbio.2006613

Cited by 17 publications

(20 citation statements)

References 65 publications

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“…Moreover, the inheritance of ciliary remnants may specify self-renewal by enhancing ciliogenesis in daughter cells following mitosis [22]. Here we showed that pathological WDR62 missense mutations caused reductions in the pool of proliferating radial glia during early-mid gestation (E12.5), premature differentiation into intermediate progenitors and immature neurons, resulting in microcephaly without overt increases in cell death which is consistent with our previous in utero knockdown studies and following conditional deletion of WDR62 in the brain [10,37]. Neural defects in WDR62 deleted or mutant mice were associated with clear ciliary abnormalities in the VZ/SVZ including increased dissociation of ciliary membranes from centrosomes which is characteristic of precocious differentiation of radial glia [9,22].…”

Section: Discussionsupporting

confidence: 90%

The association of microcephaly protein WDR62 with CPAP/IFT88 is required for cilia formation and neocortical development

Shohayeb

Yeap

et al. 2019

Human Molecular Genetics

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WDR62 mutations that result in protein loss, truncation or single amino-acid substitutions are causative for human microcephaly, indicating critical roles in cell expansion required for brain development. WDR62 missense mutations that retain protein expression represent partial loss-of-function mutants that may therefore provide specific insights into radial glial cell processes critical for brain growth. Here we utilized CRISPR/Cas9 approaches to generate three strains of WDR62 mutant mice; WDR62 V66M/V66M and WDR62R439H/R439H mice recapitulate conserved missense mutations found in humans with microcephaly, with the third strain being a null allele (WDR62stop/stop). Each of these mutations resulted in embryonic lethality to varying degrees and gross morphological defects consistent with ciliopathies (dwarfism, anophthalmia and microcephaly). We find that WDR62 mutant proteins (V66M and R439H) localize to the basal body but fail to recruit CPAP. As a consequence, we observe deficient recruitment of IFT88, a protein that is required for cilia formation. This underpins the maintenance of radial glia as WDR62 mutations caused premature differentiation of radial glia resulting in reduced generation of neurons and cortical thinning. These findings highlight the important role of the primary cilium in neocortical expansion and implicate ciliary dysfunction as underlying the pathology of MCPH2 patients.

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Section: Discussionsupporting

confidence: 90%

The association of microcephaly protein WDR62 with CPAP/IFT88 is required for cilia formation and neocortical development

Shohayeb

Yeap

et al. 2019

Human Molecular Genetics

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“…Moreover, the inheritance of ciliary remnants may specify selfrenewal by enhancing ciliogenesis in daughter cells following mitosis (Paridaen et al, 2013). Here we showed that pathological WDR62 missense mutations caused reductions in the pool of proliferating radial glia during early-mid gestation (E12.5), premature differentiation into intermediate progenitors and immature neurons, resulting in microcephaly without overt increases in cell death which is consistent with our previous in utero knockdown studies and following conditional deletion of WDR62 in the brain (Xu et al, 2018;Xu et al, 2014). Neural defects in WDR62 deleted or mutant mice were associated with clear ciliary abnormalities in the VZ/SVZ including increased dissociation of ciliary membranes from centrosomes which is characteristic of precocious differentiation of radial glia (Jayaraman et al, 2016;Paridaen et al, 2013).…”

Section: Discussionsupporting

confidence: 91%

Characterization of the microcephaly gene wd40-repeat protein 62 (wdr62) in brain growth and development

Shohayeb¹

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WD40-repeat protein 62 (WDR62) is a centrosome/microtubule-associated protein that is frequently mutated in primary microcephaly (MCPH). WDR62 has been implicated in centrosome biogenesis and spindle regulation; reinforcing the critical contribution of these processes towards carefully coordinated neural stem cell self-renewal, differentiation and neuronal migration in the expanding neocortex during development. It remains to be seen whether the range of neuronal and cellular deficits observed in animals lacking WDR62 is recapitulated with specific WDR62 missense mutations that retain protein expression. In this study, we characterized novel mouse models that recapitulate patient-identified missense mutations of WDR62 (V66M and R439H). Our results showed that V66 and R439 residues are essential to maintain self-renewal and timely neuronal differentiation during early brain development. In addition, these missense mutations caused defects in ciliogenesis in neural stem cells during early neural development. These ciliary defects resulted from a disruption in CPAP recruitment at the basal body, which is required for intra-ciliary transport of tubulin, and may contribute towards the aetiology of MCPH2. To further unravel the genetic complexity of MCPH2, we studied WDR62 functions in specific brain lineages using the power of Drosophila genetics. Unlike neural lineages, depletion of WDR62 in glia cells resulted in more severe brain growth defects causing smaller brain sizes. We also revealed a genetic interaction between WDR62 and AURKA, indicating that they act in concert in glia cells to non-autonomously promote neuroblast proliferation and brain growth. In contrast, the ectopic expression of Drosophila WDR62 in neural lineages is sufficient to promote brain overgrowth mediated through AURKA and PI3K/AKT/Myc signalling. Taken altogether, these results have provided new insights into the molecular regulation and function of WDR62 in neural stem cells and glia that are required for normal brain growth. Publications included in this thesis Shohayeb, B., et al. The association of microcephaly protein WDR62 with CPAP/IFT88 is required for cilia formation and neocortical development. Hum Mol Gen, 2019.

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“…Mitotic spindle orientation [43] Cell cycle (gastric cancer, GC) [44] Regulating intermediate neural and glial progenitors [45] Centrosome amplification (ovarian cancer, OC) [46] Cell cycle, centriole biogenesis, and mitotic spindle orientation [17] Cell growth (lung adenocarcinoma) [34] Regulating neural stem cell division [47,48]…”

Section: Mcph1 (Brit1)mentioning

confidence: 99%

“…The Chk1-Cdc25-Cdk1 pathway is disrupted in Mcph1-deficient mice, which further distorts mitotic spindle alignment and shifts the division plane of neuroprogenitors [16]. Studies on Mcph2 deficiency mice have indicated that MCPH2 mainly functions in neuron proliferation and differentiation by regulating neural stem cell division in the central nervous system [17,18,47,48]. The total number of cells and the thickness of the cortical plate were significantly decreased in Mcph5 KO mice compared with wild-type mice.…”

Section: Mcph Gene Regulate Neurogenesis and Carcinogenesis Through Rmentioning

confidence: 99%

The Yin and Yang of Autosomal Recessive Primary Microcephaly Genes: Insights from Neurogenesis and Carcinogenesis

Zhou

Zhi

et al. 2020

IJMS

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The stem cells of neurogenesis and carcinogenesis share many properties, including proliferative rate, an extensive replicative potential, the potential to generate different cell types of a given tissue, and an ability to independently migrate to a damaged area. This is also evidenced by the common molecular principles regulating key processes associated with cell division and apoptosis. Autosomal recessive primary microcephaly (MCPH) is a neurogenic mitotic disorder that is characterized by decreased brain size and mental retardation. Until now, a total of 25 genes have been identified that are known to be associated with MCPH. The inactivation (yin) of most MCPH genes leads to neurogenesis defects, while the upregulation (yang) of some MCPH genes is associated with different kinds of carcinogenesis. Here, we try to summarize the roles of MCPH genes in these two diseases and explore the underlying mechanisms, which will help us to explore new, attractive approaches to targeting tumor cells that are resistant to the current therapies.

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MEKK3 coordinates with FBW7 to regulate WDR62 stability and neurogenesis

Cited by 17 publications

References 65 publications

The association of microcephaly protein WDR62 with CPAP/IFT88 is required for cilia formation and neocortical development

The association of microcephaly protein WDR62 with CPAP/IFT88 is required for cilia formation and neocortical development

Characterization of the microcephaly gene wd40-repeat protein 62 (wdr62) in brain growth and development

The Yin and Yang of Autosomal Recessive Primary Microcephaly Genes: Insights from Neurogenesis and Carcinogenesis

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