Intermediate progenitors are increased by lengthening of the cell cycle through calcium signaling and p53 expression in human neural progenitors

Garcia-Garcia, Elisa; Pino-Barrio, María José; López-Medina, Laura; Martínez‐Serrano, Alberto

doi:10.1091/mbc.e11-06-0524

Cited by 20 publications

(22 citation statements)

References 69 publications

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“…Bcl-X L has been described to exert multiple functions in hNSCs, by molecular and cellular mechanisms involving apoptosis, changes in gene expression, control of cell cycle duration, and expansion of intermediate progenitors [34,36] Bcl-X L has been shown to act in FB and VM hNSCs in a dose-response fashion, conclusion validated by interfering RNA studies (such as those in [78] ). In the case of VM, Bcl-X L enhances the survival of A9-DAn, both in vitro and in vivo [35,36], and rescues the neurogenic potential of hVMl cells lost with passaging [36].…”

Section: Acknowledgments Integration Of Bcl-x L Effectsmentioning

confidence: 90%

“…Nevertheless, some of the properties exhibited by the cells (high input resistance, trains of action potentials, and long duration action potentials are typical of A9 SNpc DAn). In this context, Lepski et al [78] have also reported that telencephalic human neural precursors require about six weeks of in vitro differentiation to complete their electrophysiological maturation.…”

Section: Maturation Function and Maintenance Of Danmentioning

confidence: 99%

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Human midbrain precursors activate the expected developmental genetic program and differentiate long-term to functional A9 dopamine neurons in vitro. Enhancement by Bcl-XL

Seiz

Ramos-Gómez

Courtois

et al. 2012

Experimental Cell Research

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Understanding the molecular programs of the generation of human dopaminergic neurons (DAn) from their ventral mesencephalic (VM) precursors is of key importance for basic studies, progress in cell therapy, drug screening and pharmacology in the context of Parkinson's disease. The nature of human DAn precursors in vitro is poorly understood, their properties unstable, and their availability highly limited. Here we present positive evidence that human VM precursors retaining their genuine properties and long-term capacity to generate A9 type Substantia nigra human DAn (hVMl model cell line) can be propagated in culture. During a one month differentiation, these cells activate all key genes needed to progress from pro-neural and prodopaminergic precursors to mature and functional DAn. For the first time, we demonstrate that gene cascades are correctly activated during differentiation, resulting in the generation of mature DAn. These DAn have morphological and functional properties undistinguishable from those generated by VM primary neuronal cultures. In addition, we have found that the forced expression of Bcl-X L induces an increase in the expression of key developmental genes (MSX1, Abbreviations: A9-DAn, (dopaminergic neuron from the A9 group); 6-OHDA, (6-hidroxydopamine); DA, (dopamine); DAn, (dopaminergic neuron); FB, (forebrain); FP, (floor plate); hESC, (human Embryonic stem cells); hNSC, (human neural stem cells); hVM, (human ventral mesencephalon); SNpc, (substantia nigra pars compacta); TH, (tyrosine hydroxylase); VM, (ventral mesencephalon); VM DAn, (dopaminergic neuron from ventral mesencephalon); VM hNSC, (human neural stem cells from ventral mesencephalon) NGN2), maintenance of PITX3 expression temporal profile, and also enhances genes involved in DAn long-term function, maintenance and survival (ENl, LMXIB, NURRl and PITX3). As a result, Bcl-X L anticipates and enhances DAn generation.

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Section: Acknowledgments Integration Of Bcl-x L Effectsmentioning

confidence: 90%

Section: Maturation Function and Maintenance Of Danmentioning

confidence: 99%

Human midbrain precursors activate the expected developmental genetic program and differentiate long-term to functional A9 dopamine neurons in vitro. Enhancement by Bcl-XL

Seiz

Ramos-Gómez

Courtois

et al. 2012

Experimental Cell Research

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“…Furthermore, lengthening of G1 is highly correlated with the transition from apical NSCs to basal NPCs in the developing cortex (Arai et al, 2011). Similarly, lengthening the cell cycle promotes expansion of the NPC pool and enhances neuronal production in human neural progenitors (García-García et al, 2012). Moreover, as G2 lengthens during embryonic development it slows the rate of S-G2-M transition in basal NPCs, but not in apical NSCs (Calegari et al, 2005).…”

Section: Development 140 (3)mentioning

confidence: 99%

“…Moreover, several cell cycle regulators have emerged as important players in maintaining the balance between proliferative and neurogenic divisions in NSCs and NPCs (e.g. Calegari et al, 2005;Arai et al, 2011;Gruber et al, 2011;García-García et al, 2012). Cell cycle regulators form complex signaling networks that drive progression through phases of the cell cycle, and ultimately affect the length and integrity of mitosis.…”

Section: Introductionmentioning

confidence: 99%

Neural development is dependent on the function of specificity protein 2 in cell cycle progression

et al. 2013

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SUMMARYFaithful progression through the cell cycle is crucial to the maintenance and developmental potential of stem cells. Here, we demonstrate that neural stem cells (NSCs) and intermediate neural progenitor cells (NPCs) employ a zinc-finger transcription factor specificity protein 2 (Sp2) as a cell cycle regulator in two temporally and spatially distinct progenitor domains. Differential conditional deletion of Sp2 in early embryonic cerebral cortical progenitors, and perinatal olfactory bulb progenitors disrupted transitions through G1, G2 and M phases, whereas DNA synthesis appeared intact. Cell-autonomous function of Sp2 was identified by deletion of Sp2 using mosaic analysis with double markers, which clearly established that conditional Sp2-null NSCs and NPCs are M phase arrested in vivo. Importantly, conditional deletion of Sp2 led to a decline in the generation of NPCs and neurons in the developing and postnatal brains. Our findings implicate Sp2-dependent mechanisms as novel regulators of cell cycle progression, the absence of which disrupts neurogenesis in the embryonic and postnatal brain.

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“…Since IKNM is coordinated with the cell cycle, a lengthened cell cycle could explain the patterns we observed. Moreover, in view of the finding (Garcia-Garcia et al, 2012) that lengthening the cell cycle results in increased production of intermediate progenitor cells, a longer apical progenitor cell cycle in the Hsd17b7 rud cortex could be stimulating differentiation into intermediate progenitors and neurons at a faster rate.…”

Section: Discussionmentioning

confidence: 98%

Altered cholesterol biosynthesis causes precocious neurogenesis in the developing mouse forebrain

Driver

Kratz

Kelley

et al. 2016

Neurobiology of Disease

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We previously reported a mutation in the cholesterol biosynthesis gene, hydroxysteroid (17-beta) dehydrogenase 7 (Hsd17b7rudolph), that results in striking embryonic forebrain dysgenesis. Here we describe abnormal patterns of neuroprogenitor proliferation in the mutant forebrain, namely, a decrease in mitotic cells within the ventricular zone (VZ) and an increase through the remainder of the cortex by E11.5. Further evidence suggests mutant cells undergo abnormal interkinetic nuclear migration (IKNM). Furthermore, intermediate progenitors are increased at the expense of apical progenitors by E12.5, and post-mitotic neurons are expanded by E14.5. In vitro primary neuron culture further supports our model of accelerated cortical differentiation in the mutant. Combined administration of a statin and dietary cholesterol in utero achieved partial reversal of multiple developmental abnormalities in the Hsd17b7rudolph embryo, including the forebrain. These results suggest that abnormally increased levels of specific cholesterol precursors in the Hsd17b7rudolph embryo cause cortical dysgenesis by altering patterns of neurogenesis.

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Intermediate progenitors are increased by lengthening of the cell cycle through calcium signaling and p53 expression in human neural progenitors

Abstract: Calcium release in response to ATP or forced Bcl-XL expression increases the length of the cell cycle and increases the intermediate progenitors and the neuron population. The effect of calcium signaling on cell cycle control is mediated by the p53–p21 pathway.

Cited by 20 publications

References 69 publications

Human midbrain precursors activate the expected developmental genetic program and differentiate long-term to functional A9 dopamine neurons in vitro. Enhancement by Bcl-XL

Human midbrain precursors activate the expected developmental genetic program and differentiate long-term to functional A9 dopamine neurons in vitro. Enhancement by Bcl-XL

Neural development is dependent on the function of specificity protein 2 in cell cycle progression

Altered cholesterol biosynthesis causes precocious neurogenesis in the developing mouse forebrain

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