RanGAP‐mediated nucleocytoplasmic transport of Prospero regulates neural stem cell lifespan in Drosophila larval central brain

Wu, Di; Wu, Linquan; An, Huanping; Bao, Hongcun; Guo, Pengfei; Zhang, Bei; Zheng, Huimei; Zhang, Fan; Ge, Wanzhong; Cai, Yu; Xi, Yongmei; Yang, Xiaohang

doi:10.1111/acel.12854

Cited by 6 publications

(24 citation statements)

References 45 publications

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“…These features make neurons more vulnerable to the impairment of intracellular transport. The implication of defective NCT in NDs has been revealed by a variety of research model systems, including Drosophila [181,182], mouse [12,183], patient-derived induced pluripotent stem cells (iPSCs) [17,79,159,[184][185][186], and autopsy brain of patients [187]. The reported NCT-defective diseases, related mutations and possible mechanisms were summarized in Table 4.…”

Section: Figure 5 the Linkages Between Impaired Nct And Neurodegenermentioning

confidence: 99%

Nucleocytoplasmic Transport: Regulatory Mechanisms and the Implications in Neurodegeneration

Ding

Sepehrimanesh

2021

IJMS

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Nucleocytoplasmic transport (NCT) across the nuclear envelope is precisely regulated in eukaryotic cells, and it plays critical roles in maintenance of cellular homeostasis. Accumulating evidence has demonstrated that dysregulations of NCT are implicated in aging and age-related neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer’s disease (AD), and Huntington disease (HD). This is an emerging research field. The molecular mechanisms underlying impaired NCT and the pathogenesis leading to neurodegeneration are not clear. In this review, we comprehensively described the components of NCT machinery, including nuclear envelope (NE), nuclear pore complex (NPC), importins and exportins, RanGTPase and its regulators, and the regulatory mechanisms of nuclear transport of both protein and transcript cargos. Additionally, we discussed the possible molecular mechanisms of impaired NCT underlying aging and neurodegenerative diseases, such as ALS/FTD, HD, and AD.

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Section: Figure 5 the Linkages Between Impaired Nct And Neurodegenermentioning

confidence: 99%

Nucleocytoplasmic Transport: Regulatory Mechanisms and the Implications in Neurodegeneration

Ding

Sepehrimanesh

2021

IJMS

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“…Different stages of larval brains and adult brains were dissected in ice-cold Schneider’s Drosophila Medium (Gibco). Samples were fixed for 18 min in PBS (10 mM NaH2PO4/Na2HPO4, 175 mM NaCl, pH7.4) with 4% paraformaldehyde at room temperature [ 55 , 56 ]. The samples were incubated with primary antibodies at 4℃ overnight, and then with secondary antibodies at room temperature for 1–2 h. Antifade Mounting Medium (P0126, Beyotime, China) was used to protect the fluorescent signals of the samples.…”

Section: Methodsmentioning

confidence: 99%

Mxc, a Drosophila homolog of mental retardation-associated gene NPAT, maintains neural stem cell fate

Sang

Xie

et al. 2022

Cell Biosci

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Background Mental retardation is a complex neurodevelopmental disorder. NPAT, a component of the histone locus body (HLB), has been implicated as a candidate gene for mental retardation, with a mechanism yet to be elucidated. Results We identified that mxc, the Drosophila ortholog of NPAT, is required for the development of nervous system. Knockdown of mxc resulted in a massive loss of neurons and locomotion dysfunction in adult flies. In the mxc mutant or RNAi knockdown larval brains, the neuroblast (NB, also known as neural stem cell) cell fate is prematurely terminated and its proliferation potential is impeded concurrent with the blocking of the differentiation process of ganglion mother cells (GMCs). A reduction of transcription levels of histone genes was shown in mxc knockdown larval brains, accompanied by DNA double-strand breaks (DSBs). The subsidence of histone transcription levels leads to prematurely termination of NB cell fate and blockage of the GMC differentiation process. Our data also show that the increase in autophagy induced by mxc knockdown in NBs could be a defense mechanism in response to abnormal HLB assembly and premature termination of NB cell fate. Conclusions Our study demonstrate that Mxc plays a critical role in maintaining neural stem cell fate and GMC differentiation in the Drosophila larval brain. This discovery may shed light on the understanding of the pathogenesis of NPAT-related mental retardation in humans.

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“…The observation of smaller lineages of dan/danr NB clones prompted us to examine Pros location in these NBs since nuclear Pros has been considered as a typical signal for the termination of NB cell fate (Lai and Doe 2014;Wu et al 2019;Sang et al 2022). Nuclear Pros was indeed observed in the dan/danr NBs (Figures 2A -C).…”

Section: Lack Of Dan/danr Leads To Nuclear Pros In Nbsmentioning

confidence: 99%

“…Type II NBs have a smaller population (8/lobe) and express Dpn, but not Ase (Boone and Doe 2008). All of these NBs undergo proliferation at larval stages and terminate their respective stem cell fates at the early pupal stage (Maurange et al 2008;Chai et al 2013;Wu et al 2019).…”

Section: Introductionmentioning

confidence: 99%

“…Thus, one of the important roles for the maintenance of NB proliferation is to prevent the premature accumulation of Pros in the nuclei of NBs. Although it has been reported that RanGAP, a nucleocytoplasmic transport regulator, is involved in Pros accumulation in the nuclei (Wu et al 2019), the detailed regulatory mechanism of how NBs prevent premature nuclear Pros remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

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Pipsqueak family genes dan/danr antagonize nuclear Pros and prevent premature decommission of neural stem cells in Drosophila third instar larval brains

Ren

et al. 2022

Preprint

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Background Neural stem cell fate is regulated for the systematic production of a precise quantity of neurons during the development of the central nervous system. Results Here we found that two Drosophila pipsqueak family genes, distal antenna (dan) and distal antenna-related (danr), promote the proliferation of neural stem cells, termed neuroblasts (NBs), in third instar larval brains. In the absence of Dan and Danr (Dan/Danr), the NBs produce fewer daughter cells with smaller MARCM clone (lineage) sizes. The larval brain NBs in dan/danr clones show premature accumulation of nuclear Prospero (Pros), which only appears in the wildtype (wt) terminating NBs at early pupal stage. The premature nuclear Pros leads to NBs cell cycle defects and NB marker loss. Removal of Pros from dan/danr MARCM clones prevents lineage size shrinkage and rescues the loss of NB marker expression. Our data show that the appearance of nuclear Pros is behind the downregulation of Dan/Danr in the wt terminating NBs. We demonstrate that Dan/Danr and nuclear Pros are mutually exclusive in NBs. In addition, Dan/Danr are partially required for the late temporal regulator, Grainyhead (Grh), in third instar larval brain NBs. Conclusion Together our study uncovers the novel function of Dan/Danr in NB cell fate maintenance. Dan/Danr antagonize nuclear Pros, preventing NBs from premature decommission in Drosophila third instar larval brains.

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RanGAP‐mediated nucleocytoplasmic transport of Prospero regulates neural stem cell lifespan in Drosophila larval central brain

Cited by 6 publications

References 45 publications

Nucleocytoplasmic Transport: Regulatory Mechanisms and the Implications in Neurodegeneration

Nucleocytoplasmic Transport: Regulatory Mechanisms and the Implications in Neurodegeneration

Mxc, a Drosophila homolog of mental retardation-associated gene NPAT, maintains neural stem cell fate

Pipsqueak family genes dan/danr antagonize nuclear Pros and prevent premature decommission of neural stem cells in Drosophila third instar larval brains

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