Ecdysone and Mediator Change Energy Metabolism to Terminate Proliferation in Drosophila Neural Stem Cells

Homem, Catarina C.F.; Steinmann, Victoria; Burkard, Thomas R; Jais, Alexander; Esterbauer, Harald; Knoblich, Juergen A.

doi:10.1016/j.cell.2014.06.024

Cited by 201 publications

(270 citation statements)

References 85 publications

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“…1). The prominent Pkm2-to-Pkm1 switch in the embryonic brain echoes the metabolic shift from glycolysis to OXPHOS during neurogenesis (13,14). MSCs have the potential to differentiate into various cell types that display distinct metabolic properties (7).…”

Section: Discussionmentioning

confidence: 99%

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RBM4 Regulates Neuronal Differentiation of Mesenchymal Stem Cells by Modulating Alternative Splicing of Pyruvate Kinase M

Hung

et al. 2017

Molecular and Cellular Biology

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RBM4 promotes differentiation of neuronal progenitor cells and neurite outgrowth of cultured neurons via its role in splicing regulation. In this study, we further explored the role of RBM4 in neuronal differentiation. During neuronal differentiation, energy production shifts from glycolysis to oxidative phosphorylation. We found that the splice isoform change of the metabolic enzyme pyruvate kinase M (PKM) from PKM2 to PKM1 occurs during brain development and is impaired in RBM4-deficient brains. The PKM isoform change could be recapitulated in human mesenchymal stem cells (MSCs) during neuronal induction. Using a PKM minigene, we demonstrated that RBM4 plays a direct role in regulating alternative splicing of PKM. Moreover, RBM4 antagonized the function of the splicing factor PTB and induced the expression of a PTB isoform with attenuated splicing activity in MSCs. Overexpression of RBM4 or PKM1 induced the expression of neuronal genes, increased the mitochondrial respiration capacity in MSCs, and, accordingly, promoted neuronal differentiation. Finally, we demonstrated that RBM4 is induced and is involved in the PKM splicing switch and neuronal gene expression during hypoxiainduced neuronal differentiation. Hence, RBM4 plays an important role in the PKM isoform switch and the change in mitochondrial energy production during neuronal differentiation.KEYWORDS alternative splicing, hypoxia, mesenchymal stem cells, neuronal differentiation, pyruvate kinase M T he splicing regulator RBM4 modulates alternative splicing of a number of transcripts involved in cell differentiation and tumorigenesis (1, 2). Previous studies demonstrated the role of RBM4 in differentiation of muscle and pancreas cells and adipocytes (3-5). We recently reported that RBM4 is also involved in neuronal differentiation of mouse embryonal carcinoma P19 cells and neural progenitor-derived cells (1). RBM4 promotes the expression of Numb splice isoforms that function during neuronal differentiation as well as neurite outgrowth. Mesenchymal stem cells (MSCs) are adult bone marrow stromal cells that can differentiate into a variety of cell types, including neurons, and have potential in regenerative therapy for neurological diseases (6). In this study, we assessed whether RBM4 can also modulate neuronal differentiation of MSCs and explored the underlying mechanism.Cellular energy metabolism undergoes a dynamic change during development. In principle, anabolic glycolysis dominates in embryonic stem cells and permits rapid cell proliferation similar to that in cancer cells (7,8). Most adult stem cells exhibit low glycolysis activity in a quiescent state and undertake active glycolysis while proliferat-

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Section: Discussionmentioning

confidence: 99%

“…Such a metabolic switch may also be important for cell cycle exit and cell fate determination. In Drosophila melanogaster, upregulation of OXPHOS is required for terminal differentiation of neural stem cells (13). In the developing mammalian cortex, oxygen tension suppresses radial glia expansion but induces neuronal cell differentiation (14).…”

mentioning

confidence: 99%

RBM4 Regulates Neuronal Differentiation of Mesenchymal Stem Cells by Modulating Alternative Splicing of Pyruvate Kinase M

Hung

et al. 2017

Molecular and Cellular Biology

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“…D,D9 and C,C9, quantified in F). Control NBs undergo terminal differentiation at ;120 h ALH (Maurange et al 2008;Homem et al 2014). In contrast, the ectopic nerfin-1 159 Mira + cells failed to undergo timely differentiation during pupal life and continued to be highly proliferative during adult stages (indicated by pH3 + and EdU + cells compared with control) ( Fig.…”

Section: Nerfin-1 Is Expressed In Neurons Derived From Type I and Typmentioning

confidence: 99%

The transcription factor Nerfin-1 prevents reversion of neurons into neural stem cells

et al. 2015

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Cellular dedifferentiation is the regression of a cell from a specialized state to a more multipotent state and is implicated in cancer. However, the transcriptional network that prevents differentiated cells from reacquiring stem cell fate is so far unclear. Neuroblasts (NBs), the Drosophila neural stem cells, are a model for the regulation of stem cell self-renewal and differentiation. Here we show that the Drosophila zinc finger transcription factor Nervous fingers 1 (Nerfin-1) locks neurons into differentiation, preventing their reversion into NBs. Following Prospero-dependent neuronal specification in the ganglion mother cell (GMC), a Nerfin-1-specific transcriptional program maintains differentiation in the post-mitotic neurons. The loss of Nerfin-1 causes reversion to multipotency and results in tumors in several neural lineages. Both the onset and rate of neuronal dedifferentiation in nerfin-1 mutant lineages are dependent on Myc-and target of rapamycin (Tor)-mediated cellular growth. In addition, Nerfin-1 is required for NB differentiation at the end of neurogenesis. RNA sequencing (RNA-seq) and chromatin immunoprecipitation (ChIP) analysis show that Nerfin-1 administers its function by repression of selfrenewing-specific and activation of differentiation-specific genes. Our findings support the model of bidirectional interconvertibility between neural stem cells and their post-mitotic progeny and highlight the importance of the Nerfin-1-regulated transcriptional program in neuronal maintenance.

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“…This metabolic shift, which is the opposite to that observed by Otto Warburg in growing cancer cells, causes neuroblasts to reduce their growth rate. Hence, the cessation of stem cell renewal is due to a metabolic shift to oxidative phosphorylation (Homem et al, 2014). This nicely illustrates the interconnections between development and metabolism, and provides an example of how the metabolic re-wiring found in cancer is a reversal of the differentiation process observed during normal development.…”

Section: Metabolism and Metabolites Can Play Instructive Roles In Devmentioning

confidence: 89%

Metabolism meets development at Wiston House

Teleman

2016

Development

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It is becoming increasingly clear that cellular metabolite levels regulate the activity of signaling pathways, and conversely that signaling pathways affect cellular physiology and growth via metabolic pathways. Thus, metabolism and signaling mutually influence each other. The Company of Biologists' Workshop 'Metabolism in Development and Disease' brought together people studying signaling and development with people studying metabolism, particularly in a cancer context. This Meeting Review discusses examples of talks that illustrated this principle.

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Ecdysone and Mediator Change Energy Metabolism to Terminate Proliferation in Drosophila Neural Stem Cells

Cited by 201 publications

References 85 publications

RBM4 Regulates Neuronal Differentiation of Mesenchymal Stem Cells by Modulating Alternative Splicing of Pyruvate Kinase M

RBM4 Regulates Neuronal Differentiation of Mesenchymal Stem Cells by Modulating Alternative Splicing of Pyruvate Kinase M

The transcription factor Nerfin-1 prevents reversion of neurons into neural stem cells

Metabolism meets development at Wiston House

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