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Defects in the FAcilitates Chromatin Transcription (FACT) complex, a histone chaperone composed of SSRP1 and SUPT16H, are implicated in intellectual disability. Here, we reveal that the FACT complex promotes glycolysis and sustains the correct cell fate of neural stem cells/neuroblasts in the Drosophila 3rd instar larval central brain. We show that the FACT complex binds to the promoter region of the estrogen-related receptor (ERR) gene and positively regulates ERR expression. ERR is known to act as an aerobic glycolytic switch by upregulating the enzymes required for glycolysis. Dysfunction of the FACT complex leads to the downregulation of ERR transcription, resulting in a decreased ratio of glycolysis to oxidative phosphorylation (G/O) in neuroblasts. Consequently, neuroblasts exhibit smaller cell sizes, lower proliferation potential, and altered cell fates. Overexpression of ERR or suppression of mitochondrial oxidative phosphorylation in neuroblasts increases the relative G/O ratio and rescues defective phenotypes caused by dysfunction of the FACT complex. Thus, the G/O ratio, mediated by the FACT complex, plays a crucial role in neuroblast cell fate maintenance. Our study may shed light on the mechanism by which mutations in the FACT complex lead to intellectual disability in humans.
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Neural stem cell aging is a fundamental question in neurogenesis. Premature nuclear Pros is considered as an indicator of early neural stem cell aging in Drosophila. The underlying mechanism of how neural stem cells prevent premature nuclear Pros remains largely unknown. Here we identified that two pipsqueak family genes, distal antenna (dan) and distal antenna-related (danr), promote the proliferation of neural stem cells (also called neuroblasts, NBs) in third instar larval brains. In the absence of Dan and Danr (dan/danr), the NBs produce fewer daughter cells with smaller lineage sizes. The larval brain NBs in dan/danr clones show premature accumulation of nuclear Prospero (Pros), which usually appears in the terminating NBs at early pupal stage. The premature nuclear Pros leads to NBs cell cycle defects and NB identities loss. Removal of Pros from dan/danr MARCM clones prevents lineage size shrinkage and rescues the loss of NB markers. We propose that the timing of nuclear Pros is after the downregulation of dan/danr in the wt terminating NBs. dan/danr and nuclear Pros are mutually exclusive in NBs. In addition, dan/danr are also required for the late temporal regulator, Grainyhead (Grh), in third instar larval brains. Our study uncovers the novel function of dan/danr in NBs cell fate maintenance. dan/danr antagonize nuclear Pros to prevent NBs aging in Drosophila larval brains.
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Environmental stress can cause mutation or genomic instability in stem cells which, in some cases, leads to tumorigenesis. Mechanisms to monitor and eliminate these mutant stem cells remain elusive. Here, using the Drosophila larval brain as a model, we show that X-ray irradiation (IR) at the early larval stage leads to accumulation of nuclear Prospero (Pros), resulting in premature differentiation of neural stem cells (neuroblasts, NBs). Through NB-specific RNAi screenings, we determined that it is the Mre11-Rad50-Nbs1 complex and the homologous recombination (HR) repair pathway, rather than non-homologous end-joining pathway that plays, a dominant role in the maintenance of NBs under IR stress. The DNA damage sensor ATR/mei-41 is shown to act to prevent IR-induced nuclear Pros in a WRNexo-dependent manner. The accumulation of nuclear Pros in NBs under IR stress, leads to NB cell fate termination, rather than resulting in mutant cell proliferation. Our study reveals an emerging mechanism for the HR repair pathway in maintaining neural stem cell fate under irradiation stress.
Assuntos
Proteínas de Drosophila , Células-Tronco Neurais , Animais , Reparo do DNA , Drosophila/metabolismo , Mutação , Dano ao DNA , Células-Tronco Neurais/metabolismo , Endodesoxirribonucleases/genética , Endodesoxirribonucleases/metabolismo , Exodesoxirribonucleases/genética , Exodesoxirribonucleases/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Exonucleases/genética , Exonucleases/metabolismoRESUMO
BRAF mutations have been found in gliomas which exhibit abnormal electrophysiological activities, implying their potential links with the ion channel functions. In this study, we identified the Drosophila potassium channel, Slowpoke (Slo), the ortholog of human KCNMA1, as a critical factor involved in dRafGOF glioma progression. Slo was upregulated in dRafGOF glioma. Knockdown of slo led to decreases in dRafGOF levels, glioma cell proliferation, and tumor-related phenotypes. Overexpression of slo in glial cells elevated dRaf expression and promoted cell proliferation. Similar mutual regulations of p-BRAF and KCNMA1 levels were then recapitulated in human glioma cells with the BRAF mutation. Elevated p-BRAF and KCNMA1 were also observed in HEK293T cells upon the treatment of 20 mM KCl, which causes membrane depolarization. Knockdown KCNMA1 in these cells led to a further decrease in cell viability. Based on these results, we conclude that the levels of p-BRAF and KCNMA1 are co-dependent and mutually regulated. We propose that, in depolarized glioma cells with BRAF mutations, high KCNMA1 levels act to repolarize membrane potential and facilitate cell growth. Our study provides a new strategy to antagonize the progression of gliomas as induced by BRAF mutations.
Assuntos
Glioma , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta , Proteínas Proto-Oncogênicas B-raf , Animais , Humanos , Drosophila/metabolismo , Glioma/genética , Células HEK293 , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/genética , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Canais de Potássio/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismoRESUMO
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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Cold stress profoundly affects plant growth and development and is a key factor affecting the geographic distribution and evolution of plants. Plants have evolved adaptive mechanisms to cope with cold stress. Here, through the genomic analysis of Arabidopsis, three Brassica species and 17 other representative species, we found that both cold-related genes (CRGs) and their collinearity were preferentially retained after polyploidization followed by genome instability, while genome-wide gene sets exhibited a variety of other expansion mechanisms. The cold-related regulatory network was increased in Brassicaceae genomes, which were recursively affected by polyploidization. By combining our findings regarding the selective retention of CRGs from this ecological genomics study with the available knowledge of cold-induced chromosome doubling, we hypothesize that cold stress may have contributed to the success of polyploid plants through both increasing polyploidization and selectively maintaining CRGs during evolution. This hypothesis requires further biological and ecological exploration to obtain solid supporting evidence, which will potentially contribute to understanding the generation of polyploids and to the field of ecological genomics.
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The genome of kiwifruit (Actinidia chinensis) was sequenced previously, the first in the Actinidiaceae family. It was shown to have been affected by polyploidization events, the nature of which has been elusive. Here, we performed a reanalysis of the genome and found clear evidence of 2 tetraploidization events, with one occurring â¼50-57 million years ago (Mya) and the other â¼18-20 Mya. Two subgenomes produced by each event have been under balanced fractionation. Moreover, genes were revealed to express in a balanced way between duplicated copies of chromosomes. Besides, lowered evolutionary rates of kiwifruit genes were observed. These findings could be explained by the likely auto-tetraploidization nature of the polyploidization events. Besides, we found that polyploidy contributed to the expansion of key functional genes, e.g., vitamin C biosynthesis genes. The present work also provided an important comparative genomics resource in the Actinidiaceae and related families.
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A child born with spinal dysraphism and encephalocele faces the multiple and serious hazards of meningitis, hydrocephalus, paralysis and deformity of the lower limbs, and urinary bladder paralysis. The improvement in surgical management, and the advent of the shunt device for the control of hydrocephalus have so greatly altered the immediate prognosis that even a child with an extensive myelomeningocele must be considered to have a good chance of survival. We have presented a case of myelomeningocle, and two cases of meningoencephalocele and immediate repair techniques, and prognosis. 1) Surgical repair should be undertaken urgently, if possible within the first 48 hours of life and its role was the preservation of motor, sensory and intellectual function. 2) Carefully dissected the nerve filaments from the sac and replaced them into the dural canal and excised the functionless filament for prevention of spine deformity. 3) Shunt surgery should be considered before operation or immediate postoperation, in situation of huge meningoencephalocele.