Molecular mechanisms controlling cortical gliogenesis

Sauvageot, Claire; Stiles, Charles D.

doi:10.1016/s0959-4388(02)00322-7

Cited by 343 publications

(279 citation statements)

References 44 publications

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“…In the developing mammalian central nervous system, NPCs first differentiate into neurons and then into glial cells (6)(7)(8). The sequential neuron-glia lineage differentiation is preserved in hESCderived hNPCs, because we found that hNPCs initially differentiate into neurons within 30-40 days after hNPC conversion, whereas gliogenic properties emerge after prolonged culturing of hNPCs ( Fig.…”

Section: Resultsmentioning

confidence: 78%

Integrative genomic and functional analyses reveal neuronal subtype differentiation bias in human embryonic stem cell lines

Pang³

et al. 2007

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

129

113

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The self-renewal and differentiation potential of human embryonic stem cells (hESCs) suggests that hESCs could be used for regenerative medicine, especially for restoring neuronal functions in brain diseases. However, the functional properties of neurons derived from hESC are largely unknown. Moreover, because hESCs were derived under diverse conditions, the possibility arises that neurons derived from different hESC lines exhibit distinct properties, but this possibility remains unexplored. To address these issues, we developed a protocol that allows stepwise generation from hESCs of cultures composed of Ϸ70 -80% human neurons that exhibit spontaneous synaptic network activity. Comparison of neurons derived from the well characterized HSF1 and HSF6 hESC lines revealed that HSF1-but not HSF6-derived neurons exhibit forebrain properties. Accordingly, HSF1-derived neurons initially form primarily GABAergic synaptic networks, whereas HSF6-derived neurons initially form glutamatergic networks. microRNA profiling revealed significant expression differences between the two hESC lines, suggesting that microRNAs may influence their distinct differentiation properties. These observations indicate that although both HSF1 and HSF6 hESCs differentiate into functional neurons, the two hESC lines exhibit distinct differentiation potentials, suggesting that they are preprogrammed. Information on hESC line-specific differentiation biases is crucial for neural stem cell therapy and establishment of novel disease models using hESCs.microRNA ͉ neural differentiation ͉ neural stem cells ͉ synapse formation H uman embryonic stem cells (hESCs) are thought to be capable of unlimited proliferation (i.e., self-renewal), and of in vitro and in vivo differentiation into cell types originating from all three germ layers including neurons, in short, to be pluripotent (1-3). This makes hESCs perhaps the only stable and genetically tractable source of human neurons, which, besides being potentially useful for therapeutic purposes, could be invaluable for studying the function of neurological disease genes in a human genetic background (4). However, different hESC lines were established under diverse culture conditions from embryos with distinct genetic backgrounds which might endow the hESCs and their derivative neurons with distinct epigenetic and cellular properties, with obvious implications for their use in regenerative medicine. The relative properties of neurons derived from different hESC lines, however, are unknown, prompting the present study.Here, we have developed methods that allow for controlled, stepwise conversion of hESCs into cultures that contain Ͼ95% human neural stem/progenitor cells (hNPCs). The hNPCs are in turn differentiated into cultures containing 70-80% human neurons that form functional synaptic networks when cocultured with astrocytes. Using such methods, we compared neuronal sublineage differentiation and network properties of neurons derived from two NIH-registered hESC lines, HSF6 [XX, 46, National Institutes o...

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Section: Resultsmentioning

confidence: 78%

Integrative genomic and functional analyses reveal neuronal subtype differentiation bias in human embryonic stem cell lines

Pang³

et al. 2007

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

129

113

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“…Compared with neurons, glial cells act locally, so as the brain grows, their sustained small size relative to increasingly larger neurons would be compensated by the addition of larger numbers of glial cells, thereby maintaining a constant balance between total neuronal and nonneuronal mass in the brain, which we propose to be a major mechanism in driving changes in brain size. This constant balance could be achieved economically if the increased neuronal proliferation that has been proposed to drive cortical growth across species (34) led, during the development of each individual, to the generation of appropriate numbers of glial cells through the regulation of gliogenesis, which is largely postnatal (35), according to the number of neurons generated in each structure. Gliogenesis is known to be regulated by neuronal activity (31), and it has also been demonstrated that glial precursor proliferation is density-dependent and ceases once a steady-state glial density has been achieved, most likely by cell-cell contact inhibition (36).…”

Section: Discussionmentioning

confidence: 99%

Cellular scaling rules for rodent brains

Herculano‐Houzel

Mota

Lent

2006

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

458

422

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How do cell number and size determine brain size? Here, we show that, in the order Rodentia, increased size of the cerebral cortex, cerebellum, and remaining areas across six species is achieved through greater numbers of neurons of larger size, and much greater numbers of nonneuronal cells of roughly invariant size, such that the ratio between total neuronal and nonneuronal mass remains constant across species. Although relative cerebellar size remains stable among rodents, the number of cerebellar neurons increases with brain size more rapidly than in the cortex, such that the cerebellar fraction of total brain neurons increases with brain size. In contrast, although the relative cortical size increases with total brain size, the cortical fraction of total brain neurons remains constant. We propose that the faster increase in average neuronal size in the cerebral cortex than in the cerebellum as these structures gain neurons and the rapidly increasing glial numbers that generate glial mass to match total neuronal mass at a fixed glia͞neuron total mass ratio are fundamental cellular constraints that lead to the relative expansion of cerebral cortical volume across species.allometry ͉ brain size ͉ comparative neuroanatomy ͉ number of glia ͉ number of neurons B rain size varies by a factor of Ϸ100,000 across mammalian species (1, 2), and, although the cellular composition of the brain is one of the major determinants of its computational capacities (3), little is known about how the cellular composition varies with brain size. What are the cellular scaling rules that determine brain allometry? How do numbers of neuronal and nonneuronal cells contribute to structure size? What are the relative contributions of these cells across species of different brain sizes?Glia are said to be the most numerous cell type in the brain (4, 5) and to be 10-50 times more numerous than neurons in humans (6). Evidence for this assertion, however, is scant. The ratio between the total number of glial and neuronal cells (glia͞neuron ratio) in the cerebral cortex has been shown to increase with brain size (1, 7). However, the numeric expansion of glial cells relative to neurons seems to contradict the observation that the neuronal need for metabolic support remains similar across species (8). Data on how neuronal and glial cell sizes scale with brain size might help solve this discrepancy, but such data are lacking in the literature.Not much is known, either, about the total numbers of neuronal and nonneuronal cells in the brains of different species, because methodological limitations have largely restricted comparative studies of brain anatomy to analyses of volumetric data published by a small number of laboratories. Strikingly, analyses of the same data yield conflicting conclusions. For instance, although the neocortical fraction of brain volume increases from 14% in basal insectivores to 80% in humans (9), the cerebellar fraction varies little across individuals of different mammalian orders (10), a discrepancy that the latter au...

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“…In rats, the ventricular zone (VZ) arises first, and cells from this area develop mainly into neurons. VZ neurogenesis peaks at E14 and recedes at E17, whereas cells originating from the subventricular zone at late embryonic days and early postnatal life [rat E17 to postnatal day (P) 14] are destined predominantly for glial lineages (for review, see Sauvageot and Stiles, 2002). Cells were dissociated mechanically in incubation medium consisting of Eagle's MEM containing 33 mM glucose, 2 mM glutamine, 16 mg/l gentamicin, 10% horse serum (HS), and 10% FCS [growth medium (GM)].…”

Section: Methodsmentioning

confidence: 99%

In VitroIschemic Tolerance Involves Upregulation of Glutamate Transport Partly Mediated by the TACE/ADAM17-Tumor Necrosis Factor-α Pathway

Romera¹,

Hurtado²,

Botella³

et al. 2004

J. Neurosci.

117

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A short ischemic event [ischemic preconditioning (IPC)] can result in a subsequent resistance to severe ischemic injury (ischemic tolerance). Although tumor necrosis factor-␣ (TNF-␣) contributes to the brain damage found after cerebral ischemia, its expression and neuroprotective role in models of IPC have also been described. Regarding the role of TNF-␣ convertase (TACE/ADAM17), we have recently shown its upregulation in rat brain after IPC induced by transient middle cerebral artery occlusion and that subsequent TNF-␣ release accounts for at least part of the neuroprotection found in this model. We have now used an in vitro model of IPC using rat cortical cultures exposed to sublethal oxygen-glucose deprivation (OGD) to investigate TACE expression and activity after IPC and the subsequent mechanisms of ischemic tolerance. OGD-induced cell death was significantly reduced in cells exposed to IPC by sublethal OGD 24 hr before, an effect that was inhibited by the TACE inhibitor BB3103 (1 M) and anti-TNF-␣ antibody (2 g/ml) and that was mimicked by TNF-␣ (10 pg/ml) preincubation. Western blot analysis showed that TACE expression is increased after IPC. IPC caused TNF-␣ release, an effect that was blocked by the selective TACE inhibitor BB-3103. In addition, IPC diminished the increase in extracellular glutamate caused by OGD and increased cellular glutamate uptake and expression of EAAT2 and EAAT3 glutamate transporters; however, only EAAT3 upregulation was mediated by increased TNF-␣. These data demonstrate that neuroprotection induced by IPC involves upregulation of glutamate uptake partly mediated by TACE overexpression.

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Molecular mechanisms controlling cortical gliogenesis

Cited by 343 publications

References 44 publications

Integrative genomic and functional analyses reveal neuronal subtype differentiation bias in human embryonic stem cell lines

Integrative genomic and functional analyses reveal neuronal subtype differentiation bias in human embryonic stem cell lines

Cellular scaling rules for rodent brains

In VitroIschemic Tolerance Involves Upregulation of Glutamate Transport Partly Mediated by the TACE/ADAM17-Tumor Necrosis Factor-α Pathway

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