P53 is required for the developmental restriction in Müller glial proliferation in mouse retina

Ueki, Yumi; Karl, Mike O.; Sudar, Samuel; Pollak, Julia; Taylor, Richard T.; Loeffler, Kati; Wilken, Matthew S.; Reardon, Sara; Reh, Thomas A.

doi:10.1002/glia.22377

Cited by 51 publications

(81 citation statements)

References 28 publications

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“…To evaluate contributions of MCs to Lac production, we used MCs isolated from young mouse retinas and cultured for 10-14 d. During that time, MCs grow to confluence, whereas neurons degenerate (28). We incubated cultured MCs with 13 C Glc and used GC/MS to measure the appearance of M3 isotopomers of Lac and Pyr (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Pyruvate kinase and aspartate-glutamate carrier distributions reveal key metabolic links between neurons and glia in retina

Lindsay¹,

Du²,

Sloat³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

114

141

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Symbiotic relationships between neurons and glia must adapt to structures, functions, and metabolic roles of the tissues they are in. We show here that Müller glia in retinas have specific enzyme deficiencies that can enhance their ability to synthesize Gln. The metabolic cost of these deficiencies is that they impair the Müller cell's ability to metabolize Glc. We show here that the cells can compensate for this deficiency by using metabolites produced by neurons. Müller glia are deficient for pyruvate kinase (PK) and for aspartate/glutamate carrier 1 (AGC1), a key component of the malate-aspartate shuttle. In contrast, photoreceptor neurons express AGC1 and the M2 isoform of pyruvate kinase, which is commonly associated with aerobic glycolysis in tumors, proliferating cells, and some other cell types. Our findings reveal a previously unidentified type of metabolic relationship between neurons and glia. Müller glia compensate for their unique metabolic adaptations by using lactate and aspartate from neurons as surrogates for their missing PK and AGC1.glutamine metabolism | aerobic glycolysis | retina | Müller glia | photoreceptors A erobic glycolysis is a metabolic adaptation that proliferating cells use to meet anabolic demands (1, 2). In tumors, it is called the "Warburg effect." Tumors convert ∼90% of Glc they consume to lactate (Lac). The brain converts only 2-25% of the Glc it uses to Lac (3).In retinas of vertebrate animals, energy is produced in a way that resembles tumor metabolism more than brain metabolism. Aerobic glycolysis accounts for 80-96% of Glc used by retinas (4-7). Retinas are made up of neurons and glia (8). The outermost layer is occupied by photoreceptors (PRs). The inner layers are a diverse collection of signal processing neurons. Müller glia spans the thickness of the retina. The site of aerobic glycolysis in retina has not been established.Exchange of fuels is an important part of the relationship between neurons and glia (9-12). Transfer of metabolites between intracellular compartments also is important. Glycolysis is supported by reoxidation of cytosolic NADH, which can be catalyzed by lactate dehydrogenase (LDH) or by the malate-aspartate shuttle (MAS). PRs and other neurons in retinas express aspartate/glutamate carrier 1 (AGC1; also known as "Aralar") (13), a mitochondrial aspartate/glutamate carrier that has a key role in the MAS. However, Müller cells (MCs) are AGC1-deficient (13). The significance of the distribution of AGC1 has been enigmatic.Aerobic metabolism in tumors is linked to expression of the M2 isoform of pyruvate kinase, PKM2 (14, 15). Pyruvate kinase (PK) catalyzes the final step in glycolysis, synthesis of Pyr (16). Liver (PKL) and erythrocyte (PKR) isoforms are splice variants of the PKLR gene, and PKM1 and PKM2 are splice variants of the PKM gene. A unique feature of PKM2 is that it is responsive to allosteric and posttranslational regulators (16). PKM2 expression in cancer cells correlates with reduced yield of ATP from Glc and accumulation of glycolytic inte...

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Section: Resultsmentioning

confidence: 99%

“…The experiments we have described so far were done mostly with MCs dissociated from p12 retinas and cultured for 10-14 d. MCs under these conditions partially dedifferentiate (28). They retain some native characteristics but lose others.…”

Section: Asp and Lac Enhance Gln Synthesis In Cultured Mcs And In Retmentioning

confidence: 99%

Pyruvate kinase and aspartate-glutamate carrier distributions reveal key metabolic links between neurons and glia in retina

Lindsay¹,

Du²,

Sloat³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

114

141

View full text Add to dashboard Cite

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“…αPax6-cre mice (R. Ashery-Padan, Tel-Aviv University, Tel-Aviv, Israel) (Marquardt et al, 2001) were crossed to R26-stop-flox-rtTA mice (Jackson) (Belteki et al, 2005). NMDA damage was performed as previously described (Ueki et al, 2012). Tamoxifen (Sigma) was administered intraperitoneally at 100 mg/kg in corn oil.…”

Section: Animalsmentioning

confidence: 99%

“…MG from postnatal day (P)12 mice were cultured [Neurobasal + N2, epidermal growth factor (EGF), 10% fetal bovine serum (FBS)] as previously described (Ueki et al, 2012) with 1 μM 5-ethynyl-2Ј-deoxyuridine (EdU). Lentiviral particles were added in Optimem (Gibco) or neural medium (Neurobasal + N2, B27, 1% tetracycline (tet)-free FBS), and 3-6 hours later medium was replaced.…”

Section: Dissociated Mg Culturementioning

confidence: 99%

ASCL1 reprograms mouse Müller glia into neurogenic retinal progenitors

et al. 2013

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SUMMARYNon-mammalian vertebrates have a robust ability to regenerate injured retinal neurons from Müller glia (MG) that activate the gene encoding the proneural factor Achaete-scute homolog 1 (Ascl1; also known as Mash1 in mammals) and de-differentiate into progenitor cells. By contrast, mammalian MG have a limited regenerative response and fail to upregulate Ascl1 after injury. To test whether ASCL1 could restore neurogenic potential to mammalian MG, we overexpressed ASCL1 in dissociated mouse MG cultures and intact retinal explants. ASCL1-infected MG upregulated retinal progenitor-specific genes and downregulated glial genes. Furthermore, ASCL1 remodeled the chromatin at its targets from a repressive to an active configuration. MG-derived progenitors differentiated into cells that exhibited neuronal morphologies, expressed retinal subtype-specific neuronal markers and displayed neuron-like physiological responses. These results indicate that a single transcription factor, ASCL1, can induce a neurogenic state in mature MG.

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“…S3). However, postnatal MG that are forced to re-enter the cell cycle, either by the administration of mitogenic factors or in response to retinal injury, are capable of undergoing interkinetic nuclear migration (INM) and cell division (Close et al, 2006;Joly et al, 2011;Karl et al, 2008;Ueki et al, 2012). SOX2 is crucial to cell cycle dynamics in the retina, cortical subventricular zone and in glial cells in the hippocampus (Pevny and Nicolis, 2010;Ferri et al, 2004).…”

Section: Sox2mentioning

confidence: 99%

SOX2 maintains the quiescent progenitor cell state of postnatal retinal Müller glia

et al. 2013

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SUMMARYWithin discrete regions of the developing mammalian central nervous system, small subsets of glia become specialized to function as neural stem cells. As a result of their self-renewal and neurogenic capacity, these cells later serve to replenish neurons and glia during persistent or injury-induced adult neurogenesis. SOX2, an HMG box transcription factor, plays an essential role in the maintenance of both embryonic and adult neural progenitors. It is unclear, however, which biological mechanisms regulated by SOX2 are required for neural stem cell maintenance. In this study, we address this question through genetic analysis of SOX2 function in differentiating postnatal Müller glia, a cell type that maintains neurogenic capacity in the adult retina. By utilizing molecular analysis and real-time imaging, we show that two progenitor characteristics of nascent Müller glia -their radial morphology and cell cycle quiescence -are disrupted following conditional genetic ablation of Sox2 in the mouse postnatal retina, leading to Müller cell depletion and retinal degeneration. Moreover, we demonstrate that genetic induction of the Notch signaling pathway restores Müller glial cell identity to Sox2 mutant cells, but does not secure their quiescent state. Collectively, these results uncouple the roles of SOX2 and the Notch signaling pathway in the postnatal retina, and uncover a novel role for SOX2 in preventing the depletion of postnatal Müller glia through terminal cell division.

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P53 is required for the developmental restriction in Müller glial proliferation in mouse retina

Cited by 51 publications

References 28 publications

Pyruvate kinase and aspartate-glutamate carrier distributions reveal key metabolic links between neurons and glia in retina

Pyruvate kinase and aspartate-glutamate carrier distributions reveal key metabolic links between neurons and glia in retina

ASCL1 reprograms mouse Müller glia into neurogenic retinal progenitors

SOX2 maintains the quiescent progenitor cell state of postnatal retinal Müller glia

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