Stox1 as a novel transcriptional suppressor of Math1 during cerebellar granule neurogenesis and medulloblastoma formation

Zhang, Chenlu; Ji, Zhongzhong; Wang, Minglei; Zhang, Weiwei; Yang, Rong; An, Huanping; Yang, Ru; Abel, Daan van; Dijk, Marie van; Yang, Xiaohang; Ou, Guangshuo; Zhu, Helen He; Gao, Wei‐Qiang

doi:10.1038/cdd.2016.85

Cited by 14 publications

(17 citation statements)

References 54 publications

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“…17,18 Mice used in all these experiments were raised in the specific pathogen-free animal centre at Renji Hospital, Shanghai Jiaotong University. 17,18 Mice used in all these experiments were raised in the specific pathogen-free animal centre at Renji Hospital, Shanghai Jiaotong University.…”

Section: Animal and Treatmentsmentioning

confidence: 99%

“…The EGL was examined by haematoxylin and eosin staining (H&E staining) (Figure 1A-D) as well as for GNP marker Math1 + cells (Figure 1F-K) [17][18][19][20][21]. While with high concentration (100 mg/ kg), the mice could not survive to adulthood, we specifically gave a single intraperitoneal injection (50 mg/kg) of CTX or PBS 9 as a control to mice at postnatal day 6 (P6).…”

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confidence: 99%

“…To determine possible neurotoxic effects of CTX on newborn mouse cerebella, we first assessed possible histological changes in the cerebellar EGL at the stage of cerebellar development following administration of CTX. Math1-GFP transgenic mouse line was used to detect Math1 expression rather than using an antibody against Math1 17,18. Both PBS-treated (Con) and CTX-treated (CTX) mice were sacrificed at P8, 48 hours after the injection.…”

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confidence: 99%

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Histological, cellular and behavioural analyses of effects of chemotherapeutic agent cyclophosphamide in the developing cerebellum

Luo

Tang

et al. 2019

Cell Proliferation

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Objectives:We performed histological, cellular and behavioural analyses of the effects of cyclophosphamide (CTX), a chemotherapeutic drug, in the developing cerebellum and aimed to provide valuable insights into clinical application of CTX in children.Materials and methods: C57BL/6 mice and Math1-dependent GFP expression transgenic mice were used in the research. H&E staining was performed to analyse histological effects of CTX in the cerebellum. Staining for EdU and TUNEL was used to estimate the cell proliferation and apoptosis. Rotarod test and hanging wire test were used to evaluate the behavioural functions. Immunofluorescent staining was used to identify the cell types. The differentiation markers and genes related to Sonic Hedgehog (SHH) signalling were measured via quantitative real-time PCR or immunoblotting. Results:We found that while CTX induced a significant reduction in cell proliferation and increased apoptosis in the EGL in 48 hours, the behavioural functions and the multilayer laminar structure of cerebella were largely restored when the mice grew to adults. Mechanistically, granule neuron progenitors, driven by the SHH signalling, enhanced the capability of proliferation quickly after CTX administration was stopped, which allowed the developing cerebellum to catch up and to gradually replenish the injury. Conclusion:The chemotherapeutic agent CTX induces an immediate damage to the developing cerebellum, but the cerebellar multilayer laminar structure and motor function can be largely restored if the agent is stopped shortly after use.

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Section: Animal and Treatmentsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Histological, cellular and behavioural analyses of effects of chemotherapeutic agent cyclophosphamide in the developing cerebellum

Luo

Tang

et al. 2019

Cell Proliferation

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“…As might be expected, CCAAT/enhancer‐binding protein δ (Cebpd), a transcription factor that is a member of the CCAAT/enhancer‐binding protein family, is expressed in the brain throughout development and into adulthood and has been shown to play regulatory roles in neuroinflammation, learning, and memory, was downregulated in the cerebellum 28,29 . Other transcription factors, such as storkhead box 1 (Stox1), which is a forkhead transcriptional factor that plays a pivotal role in cerebellar granule neurogenesis is upregulated along with GCP differentiation and repressed by activation of sonic hedgehog (SHH) signaling, were differentially expressed 30 …”

Section: Resultsmentioning

confidence: 99%

Ccdc134 deficiency impairs cerebellar development and motor coordination

Yin

Liao

Wang

et al. 2021

Genes Brain and Behavior

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Coiled-coil domain containing 134 (CCDC134) has been shown to serve as an immune cytokine to exert antitumor effects and to act as a novel regulator of hADA2a to affect PCAF acetyltransferase activity. While Ccdc134 loss causes abnormal brain development in mice, the significance of CCDC134 in neuronal development in vivo is controversial. Here, we report that CCDC134 is highly expressed in Purkinje cells (PCs) at all developmental stages and regulates mammalian cerebellar development in a cell type-specific manner. Selective deletion of Ccdc134 in mouse neural stem cells (NSCs) caused defects in cerebellar morphogenesis, including a decrease in the number of PCs and impairment of PC dendritic growth, as well as abnormal granule cell development. Moreover, loss of Ccdc134 caused progressive motor dysfunction with deficits in motor coordination and motor learning. Finally, Ccdc134 deficiency inhibited Wnt signaling but increased Ataxin1 levels. Our findings provide evidence that CCDC134 plays an important role in cerebellar development, possibly through regulating Wnt signaling and Ataxin1 expression levels, and in controlling cerebellar function for motor coordination and motor learning, ultimately making it a potential contributor to cerebellar pathogenesis.

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“…The presence of the Storkhead box, a winged-helix domain, suggests that HAM-1 is a transcription factor. Stox1, one of the two mammalian proteins containing a Storkhead box, has been shown to directly regulate transcription of target genes [33,34]. Our finding that the transgene likely used in the ModEncode experiments to identify HAM-1 binding sites is a mep-1::gfp fusion reveals that there is currently no evidence for HAM-1 in transcription.…”

Section: The Role Of Ham-1 In Dcsamentioning

confidence: 97%

The Caenorhabditis elegans HAM-1 protein modifies G protein signaling and membrane extension to reverse the polarity of asymmetric cell division

Teulière

Garriga

2018

Preprint

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Asymmetric divisions often produce daughter cells that differ in both fate and size. The Caenorhabditis elegans HAM-1 protein regulates both daughter cell fate and daughter cell size asymmetry (DCSA) in a subset of asymmetric divisions. Here we focus on the divisions of the Q.a and Q.p neuroblasts, which use distinct mechanisms to divide with opposite polarity. Q.a divides by a ham-1-dependent, spindle-independent, myosindependent mechanism to produce a smaller anterior daughter that dies, whereas Q.p divides by a ham-1-independent, spindle-dependent, myosin-independent mechanism to produce a smaller posterior daughter that dies. Despite these differences, we found that membrane extension at the posterior of Q.a and at the anterior of Q.p promoted DCSA in these cells by a Wiscott-Aldrich protein (WASp)-dependent mechanism and that in ham-1 mutant Q.a divisions, the polarity of this extension was reversed. In addition, the spindle moved posteriorly during the Q.a division in a ham-1 mutant, a phenotype normally exhibited by Q.p. We found that this spindle movement in wild-type Q.p divisions required Ga proteins that promote spindle movement in other asymmetric divisions, and GPR-1, a protein involved in linking G proteins to microtubule asters, localized to the posterior cortex of Q.p. Genetic interactions suggest that ham-1 mutant Q.a divisions also require Ga proteins function to divide with a reversed polarity. The transformation of Q.a to Q.p-like polarity in the ham-1 mutant, however, appeared incomplete: ham-1 loss did not alter the asymmetric localization of the non-muscle myosin NMY-2 to the anterior cortex of Q.a. A GFP tagged ham-1 transgene revealed that Q.a but not Q.p expressed ham-1. Finally, we show that HAM-1 has both cortical and nuclear functions in Q,a DCSA. We propose a model where HAM-1 modifies a default Q.p-type polarity by localizing WASp function to the posterior Q.a membrane and by interfering with G-protein mediated spindle movement. Author SummaryOne way that animals produce different cell types is by asymmetric cell division, where a cell divides to produce daughter cells that differ in fate. Much is known about the mechanisms that polarize dividing cells to generate daughters that differ in fate. Some asymmetric cell divisions also result in daughters that differ in size, and the mechanisms that regulate how cells generate an asymmetric cleavage plane are poorly understood.In neural progenitors of the nematode Caenorhabditis elegans, two distinct mechanisms generate daughter cells of different size. One type requires movement of the mitotic spindle, which then defines the plane of the cell division. The other is spindleindependent. Here, we study two cells that divide with opposite polarities using these two mechanisms. We find that in the absence of the protein HAM-1, which has been reported to regulate gene transcription, the cell that normally divides using a spindleindependent mechanism now divides with a reversed polarity using a spindle-dependent mechanism. Our findings suggest ...

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Stox1 as a novel transcriptional suppressor of Math1 during cerebellar granule neurogenesis and medulloblastoma formation

Cited by 14 publications

References 54 publications

Histological, cellular and behavioural analyses of effects of chemotherapeutic agent cyclophosphamide in the developing cerebellum

Histological, cellular and behavioural analyses of effects of chemotherapeutic agent cyclophosphamide in the developing cerebellum

Ccdc134 deficiency impairs cerebellar development and motor coordination

The Caenorhabditis elegans HAM-1 protein modifies G protein signaling and membrane extension to reverse the polarity of asymmetric cell division

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