Optic Nerve Alterations in P27<sup>Kip1</sup>Knockout Mice

López-Sánchez, E.; Francés-Muñoz, Ester; Chaques, V.; Sanchez-Benavent, M. L.; Menezo, J.L.

doi:10.1177/112067210701700317

Cited by 3 publications

(4 citation statements)

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“…Moreover, the migratory and differentiation capabilities of glial progenitors are perturbed during E13 to E19 in p27 KIP1 null mice, as there were significant increases in QKI-positive; BrdU-positive cells in the subventricular zone compared to wild-type controls [42]. In addition, reduction in MBP staining is observed in p27 KIP1 knockout mice in the optic nerve, consistent with the requirement for p27 KIP1 and PNS myelination [43]. We have previously showed that p27 KIP1 increases after the ectopic expression of QKI-6/7 in oligodendrocytes [8].…”

Section: Discussionmentioning

confidence: 94%

The QKI-6 and QKI-7 RNA Binding Proteins Block Proliferation and Promote Schwann Cell Myelination

et al. 2009

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BackgroundThe quaking viable (qkv) mice have uncompacted myelin in their central and peripheral nervous system (CNS, PNS). The qk gene encodes 3 major alternatively spliced isoforms that contain unique sequence at their C-terminus dictating their cellular localization. QKI-5 is a nuclear isoform, whereas QKI-6 and QKI-7 are cytoplasmic isoforms. The qkv mice harbor an enhancer/promoter deletion that prevents the expression of isoforms QKI-6 and QKI-7 in myelinating cells resulting in a dysmyelination phenotype. It was shown that QKI regulates the differentiation of oligodendrocytes, the myelinating cells of the CNS, however, little is known about the role of the QKI proteins, or RNA binding proteins in PNS myelination.Methodology/Principal FindingsTo define the role of the QKI proteins in PNS myelination, we ectopically expressed QKI-6 and QKI-7 in primary rat Schwann cell/neuron from dorsal root ganglia cocultures. We show that the QKI isoforms blocked proliferation and promoted Schwann cell differentiation and myelination. In addition, these events were coordinated with elevated proteins levels of p27KIP1 and myelin basic protein (MBP), markers of Schwann cell differentiation. QKI-6 and QKI-7 expressing co-cultures contained myelinated fibers that had directionality and contained significantly thicker myelin, as assessed by electron microscopy. Moreover, QKI-deficient Schwann cells had reduced levels of MBP, p27KIP1 and Krox-20 mRNAs, as assessed by quantitative RT-PCR.Conclusions/SignificanceOur findings suggest that the QKI-6 and QKI-7 RNA binding proteins are positive regulators of PNS myelination and show that the QKI RNA binding proteins play a key role in Schwann cell differentiation and myelination.

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Section: Discussionmentioning

confidence: 94%

The QKI-6 and QKI-7 RNA Binding Proteins Block Proliferation and Promote Schwann Cell Myelination

et al. 2009

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“…It is expressed in many adult glial populations including Schwann cells, cortical astrocytes, spinal cord astrocytes, oligodendrocytes, and retinal Müller glia [23-27]. In germline p27-deficient mice ( p27 -/- ), adult glia can display hallmarks of reactive gliosis [24-26,28]. In the wild-type retina, quiescent Müller glia normally do not express the intermediate filament glial fibrillary acidic protein (GFAP), but Müller glia in p27 -/- mice express high levels of GFAP and in some instances migrate into the subretinal space [24,26].…”

Section: Introductionmentioning

confidence: 99%

Proliferative reactive gliosis is compatible with glial metabolic support and neuronal function

et al. 2011

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BackgroundThe response of mammalian glial cells to chronic degeneration and trauma is hypothesized to be incompatible with support of neuronal function in the central nervous system (CNS) and retina. To test this hypothesis, we developed an inducible model of proliferative reactive gliosis in the absence of degenerative stimuli by genetically inactivating the cyclin-dependent kinase inhibitor p27Kip1 (p27 or Cdkn1b) in the adult mouse and determined the outcome on retinal structure and function.Resultsp27-deficient Müller glia reentered the cell cycle, underwent aberrant migration, and enhanced their expression of intermediate filament proteins, all of which are characteristics of Müller glia in a reactive state. Surprisingly, neuroglial interactions, retinal electrophysiology, and visual acuity were normal.ConclusionThe benign outcome of proliferative reactive Müller gliosis suggests that reactive glia display context-dependent, graded and dynamic phenotypes and that reactivity in itself is not necessarily detrimental to neuronal function.

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“…47 ), in the murine retina p27 Kip1 is also expressed by precursor cells during late G2/early G1. 65 The expression of p27 Kip1 in the mouse retinal precursors may explain both the increase of RGC axons in the optic nerve 66 and the retinal dysplasia [67][68][69] observed in p27 Kip1¡/¡ mice. Nevertheless, the increase of RGC number in the retina of p27 Kip1¡/¡ mice that would explain this phenotype is not dramatic, 66 and seems to be compensated by apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…65 The expression of p27 Kip1 in the mouse retinal precursors may explain both the increase of RGC axons in the optic nerve 66 and the retinal dysplasia [67][68][69] observed in p27 Kip1¡/¡ mice. Nevertheless, the increase of RGC number in the retina of p27 Kip1¡/¡ mice that would explain this phenotype is not dramatic, 66 and seems to be compensated by apoptosis. 44,65 In this context, interfering RNA against p27 Kip1 has been shown to induce cell death in cultured cortical neurons.…”

Section: Discussionmentioning

confidence: 99%

p27^Kip1participates in the regulation of endoreplication in differentiating chick retinal ganglion cells

Ovejero‐Benito

Frade

2015

Cell Cycle

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Nuclear DNA duplication in the absence of cell division (i.e. endoreplication) leads to somatic polyploidy in eukaryotic cells. In contrast to some invertebrate neurons, whose nuclei may contain up to 200,000-fold the normal haploid DNA amount (C), polyploid neurons in higher vertebrates show only 4C DNA content. To explore the mechanism that prevents extra rounds of DNA synthesis in these latter cells we focused on the chick retina, where a population of tetraploid retinal ganglion cells (RGCs) has been described. We show that differentiating chick RGCs that express the neurotrophic receptors p75 and TrkB while lacking retinoblastoma protein, a feature of tetraploid RGCs, also express p27 Kip1 . Two different short hairpin RNAs (shRNA) that significantly downregulate p27 Kip1 expression facilitated DNA synthesis and increased ploidy in isolated chick RGCs. Moreover, this forced DNA synthesis could not be prevented by Cdk4/6 inhibition, thus suggesting that it is triggered by a mechanism similar to endoreplication. In contrast, p27 Kip1 deficiency in mouse RGCs does not lead to increased ploidy despite previous observations have shown ectopic DNA synthesis in RGCs from p27 Kip1¡/¡ mice. This suggests that a differential mechanism is used for the regulation of neuronal endoreplication in mammalian versus avian RGCs.

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Optic Nerve Alterations in P27^Kip1Knockout Mice

Abstract: The morphologic and morphometric results suggest that homozygous P27(Kip1) knock-out mice had hypertrophic, hyperplastic, and dystrophic ON.

Cited by 3 publications

References 20 publications

The QKI-6 and QKI-7 RNA Binding Proteins Block Proliferation and Promote Schwann Cell Myelination

The QKI-6 and QKI-7 RNA Binding Proteins Block Proliferation and Promote Schwann Cell Myelination

Proliferative reactive gliosis is compatible with glial metabolic support and neuronal function

p27^Kip1participates in the regulation of endoreplication in differentiating chick retinal ganglion cells

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Optic Nerve Alterations in P27Kip1Knockout Mice

Abstract: The morphologic and morphometric results suggest that homozygous P27(Kip1) knock-out mice had hypertrophic, hyperplastic, and dystrophic ON.

Cited by 3 publications

References 20 publications

The QKI-6 and QKI-7 RNA Binding Proteins Block Proliferation and Promote Schwann Cell Myelination

The QKI-6 and QKI-7 RNA Binding Proteins Block Proliferation and Promote Schwann Cell Myelination

Proliferative reactive gliosis is compatible with glial metabolic support and neuronal function

p27Kip1participates in the regulation of endoreplication in differentiating chick retinal ganglion cells

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Optic Nerve Alterations in P27^Kip1Knockout Mice

p27^Kip1participates in the regulation of endoreplication in differentiating chick retinal ganglion cells