p27<sup>kip1</sup> independently promotes neuronal differentiation and migration in the cerebral cortex

Nguyen, Laurent; Besson, Arnaud; Heng, Julian Ik‐Tsen; Schuurmans, Carol; Teboul, Lydia; Parras, Carlos; Philpott, Anna; Roberts, James M.; Guillemot, François

doi:10.1101/gad.377106

Cited by 341 publications

(450 citation statements)

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“…The coactivator CBP has been shown to be critical for Mash1 activity, whereas the Id family of bHLH-interacting proteins repress the activity of bHLH transcription factors. 39 Earlier studies have shown that p27Kip2 and Neurogenin2 (Ngn2) interacts in the dorsal pallium and developing neocortex 14,17 suggesting in addition to the temporal aspects, a spatial component in the expression and function of different CKIs Reporter gene assays. The E-box reporter plasmid containing region of the MCK enhancer coupled to luciferase, MCK-fos-luc was a gift from Dr. M Sigvardsson.…”

Section: Methodsmentioning

confidence: 99%

“…11,12 In addition, CDK-inhibitors (CKIs) have been shown to play active roles in neural differentiation and migration. 10,13,14 The expression of p21Cip1 in the developing telencephalon is relatively low, but it has been reported that p21Cip1 is essential for the maintenance of adult neural progenitors in the forebrain. 15 p27Kip1 has been implicated in the cell-cycle arrest of neural precursors during forebrain development, and also in oligodendrocytic specification and differentiation.…”

mentioning

confidence: 99%

“…10,16 More recently, it has been demonstrated that p27Kip1 plays an important role in regulating neuronal migration in the developing neocortex. 14,17 In addition, p27Kip1 exerts a direct effect on neuronal differentiation by increasing the stability of the neurogenic bHLH factor Ngn2. 14 The role for p57Kip2 in brain development is less clear, despite the fact that p57Kip2 is the only CKI of the Cip/Kip family that is absolutely required for survival.…”

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confidence: 99%

“…14,17 In addition, p27Kip1 exerts a direct effect on neuronal differentiation by increasing the stability of the neurogenic bHLH factor Ngn2. 14 The role for p57Kip2 in brain development is less clear, despite the fact that p57Kip2 is the only CKI of the Cip/Kip family that is absolutely required for survival. 18 p57Kip2 has been implicated in the control of neural precursor proliferation at several levels of the developing nervous system, 11,19 and recent in vivo studies have established that the correct expression levels of p57Kip2 is required for proper development of the developing spinal cord.…”

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confidence: 99%

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p57Kip2 is a repressor of Mash1 activity and neuronal differentiation in neural stem cells

et al. 2009

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Mammalian central nervous system (CNS) development is a highly organized process involving the precise and coordinated timing of cell-cycle exit, differentiation, survival, and migration. These events require proper expression of pro-neuronal genes but also repression of alternative cell fates and restriction of cell-type-specific gene expression. Here, we show that the cyclindependent kinase (CDK) inhibitor p57Kip2 interacted with pro-neuronal basic helix-loop-helix (bHLH) factors such as Mash1, NeuroD, and Nex/Math2. Increased levels of p57Kip2 inhibited Mash1 transcriptional activity independently of CDK interactions and acted as a direct repressor in transcriptional assays. Proliferating telencephalic neural progenitors co-expressed basal levels of Mash1 and p57Kip2, and endogenous p57Kip2 accumulated transiently in the nuclei of neural stem cells (NSCs) during early stages of astrocyte differentiation mediated by ciliary neurotrophic factor (CNTF), independent of cell-cycle exit and at times when Mash1 expression was still prominent. In accordance with these observations, gain-and loss-of-function studies showed that p57Kip2 repressed neuronal differentiation after mitogen withdrawal, but exerted little or no effect on CNTFmediated astroglial differentiation of NSCs. Our data suggest a novel role for p57Kip2 as a context-dependent repressor of neurogenic transcription factors and telencephalic neuronal differentiation. The development of the mammalian central nervous system (CNS) critically relies on a tight coordination among cell proliferation, survival, migration, and differentiation. 1,2 Proper neuronal differentiation does not only require pro-neuronal genes but also regulated repression of other cell fates, such as glial differentiation. 2 Thus, early neural progenitors preferentially differentiate into neurons and do not respond properly to astrocyte-inducing cytokines, at least in part due to DNA methylation of astrocyte-characteristic genes such as glial fibrillary acidic protein (GFAP). 3,4 In line with these observations, it has been shown that loss of the DNA methyl transferase DNMT1 results in hypomethylation and precocious onset of astrocytic genes at the expense of neurogenesis in early neural precursors. 5 In later progenitors, astrocytic genes become demethylated. 3,4 Transcriptional repression of astrocytic genes and thus the correct numbers of progenitors and neurons at these late events, instead depends on other factors such as the Notch-regulated transcription factor CSL/RBP-Jk and the co-repressors N-CoR and SMRT. 6,7 In addition, neurogenic members of the basic helix-loop-helix (bHLH) family of transcription factors, such as Mash1 and Neurogenin (Ngn) 2, interferes with astrocyte differentiation in multipotent neural progenitors at least in part by sequestering the coactivators CBP/p300 required for astrocyte differentiation. 8 Less is understood regarding a corresponding repression of neuronal differentiation during glial differentiation. Hes transcription factors repress neurogenic ...

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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p57Kip2 is a repressor of Mash1 activity and neuronal differentiation in neural stem cells

et al. 2009

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“…Nevertheless, p27 Kip1 can also participate in the blockage of classical cell cycle progression 9 as well as neuronal differentiation and migration. 71 Therefore, p27 Kip1 is probably playing multiple roles in RGCs, including the blockade of tetraploid neurons to undergo extra rounds of endoreplication and the inhibition of cell cycle reactivation in diploid neurons that have not been programmed to become tetraploid.…”

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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Emerging roles of metazoan cell cycle regulators as coordinators of the cell cycle and differentiation

2020

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In multicellular organisms, cell proliferation must be tightly coordinated with other developmental processes to form functional tissues and organs. Despite significant advances in our understanding of how the cell cycle is controlled by conserved cell‐cycle regulators (CCRs), how the cell cycle is coordinated with cell differentiation in metazoan organisms and how CCRs contribute to this process remain poorly understood. Here, we review the emerging roles of metazoan CCRs as intracellular proliferation‐differentiation coordinators in multicellular organisms. We illustrate how major CCRs regulate cellular events that are required for cell fate acquisition and subsequent differentiation. To this end, CCRs employ diverse mechanisms, some of which are separable from those underpinning the conventional cell‐cycle‐regulatory functions of CCRs. By controlling cell‐type‐specific specification/differentiation processes alongside the progression of the cell cycle, CCRs enable spatiotemporal coupling between differentiation and cell proliferation in various developmental contexts in vivo. We discuss the significance and implications of this underappreciated role of metazoan CCRs for development, disease and evolution.

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p27^kip1 independently promotes neuronal differentiation and migration in the cerebral cortex

Cited by 341 publications

References 54 publications

p57Kip2 is a repressor of Mash1 activity and neuronal differentiation in neural stem cells

p57Kip2 is a repressor of Mash1 activity and neuronal differentiation in neural stem cells

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

Emerging roles of metazoan cell cycle regulators as coordinators of the cell cycle and differentiation

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p27kip1 independently promotes neuronal differentiation and migration in the cerebral cortex

Cited by 341 publications

References 54 publications

p57Kip2 is a repressor of Mash1 activity and neuronal differentiation in neural stem cells

p57Kip2 is a repressor of Mash1 activity and neuronal differentiation in neural stem cells

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

Emerging roles of metazoan cell cycle regulators as coordinators of the cell cycle and differentiation

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p27^kip1 independently promotes neuronal differentiation and migration in the cerebral cortex

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