Dataset Information

Rp58 and p27^kip1 coordinate cell cycle exit and neuronal migration within the embryonic mouse cerebral cortex.

ABSTRACT:

Background

During the development of the mammalian cerebral cortex, newborn postmitotic projection neurons are born from local neural stem cells and must undergo radial migration so as to position themselves appropriately to form functional neural circuits. The zinc finger transcriptional repressor Rp58 (also known as Znf238 or Zbtb18) is critical for coordinating corticogenesis, but its underlying molecular mechanism remains to be better characterised.

Findings

Here, we demonstrate that the co-expression of Rp58 and the cyclin dependent kinase inhibitor (CDKI) p27^kip1 is important for E14.5-born cortical neurons to coordinate cell cycle exit and initiate their radial migration. Notably, we find that the impaired radial positioning of Rp58-deficient cortical neurons within the embryonic (E17.5) mouse cortex, as well as their multipolar to bipolar transition from the intermediate zone to the cortical plate can be restored by forced expression of p27^kip1 in concert with suppression of Rnd2, a downstream target gene of Rp58. Furthermore, the restorative effects of p27^kip1 and Rnd2 abrogation are reminiscent of suppressing RhoA signalling in Rp58-deficient cells.

Conclusions

Our findings demonstrate functional interplay between a transcriptional regulator and a CDKI to mediate neuroprogenitor cell cycle exit, as well as to promote radial migration through a molecular mechanism consistent with suppression of RhoA signalling.

SUBMITTER: Clement O

PROVIDER: S-EPMC5433244 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Publications

Rp58 and p27<sup>kip1</sup> coordinate cell cycle exit and neuronal migration within the embryonic mouse cerebral cortex.

Clément Olivier O Hemming Isabel Anne IA Gladwyn-Ng Ivan Enghian IE Qu Zhengdong Z Li Shan Shan SS Piper Michael M Heng Julian Ik-Tsen JI

Neural development 20170515 1

<h4>Background</h4>During the development of the mammalian cerebral cortex, newborn postmitotic projection neurons are born from local neural stem cells and must undergo radial migration so as to position themselves appropriately to form functional neural circuits. The zinc finger transcriptional repressor Rp58 (also known as Znf238 or Zbtb18) is critical for coordinating corticogenesis, but its underlying molecular mechanism remains to be better characterised.<h4>Findings</h4>Here, we demonstra ...[more]

PMID: 28506232

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Project description:BackgroundPoly C Binding Protein 1 (PCBP1) is an RNA-binding protein that binds and regulates translational activity of subsets of cellular mRNAs. Depletion of PCBP1 is implicated in various carcinomas, but the underlying mechanism in tumorigenesis remains elusive.MethodsWe performed a transcriptome-wide screen to identify novel bounding mRNA of PCBP1. The bind regions between PCBP1 with target mRNA were investigated by using point mutation and luciferase assay. Cell proliferation, cell cycle, tumorigenesis and cell apoptosis were also evaluated in ovary and colon cancer cell lines. The mechanism that PCBP1 affects p27 was analyzed by mRNA stability and ribosome profiling assays. We analyzed PCBP1 and p27 expression in ovary, colon and renal tumor samples and adjacent non-tumor tissues using RT-PCR, Western Blotting and immunohistochemistry. The prognostic significance of PCBP1 and p27 also analyzed using online databases.ResultsWe identified cell cycle inhibitor p27Kip1 (p27) as a novel PCBP1-bound transcript. We then demonstrated that binding of PCBP1 to p27 3'UTR via its KH1 domain mainly stabilizes p27 mRNA, while enhances its translation to fuel p27 expression, prior to p27 protein degradation. The upregulated p27 consequently inhibits cell proliferation, cell cycle progression and tumorigenesis, whereas promotes cell apoptosis under paclitaxel treatment. Conversely, knockdown of PCBP1 in turn compromises p27 mRNA stability, leading to lower p27 level and tumorigenesis in vivo. Moreover, forced depletion of p27 counteracts the tumor suppressive ability of PCBP1 in the same PCBP1 over-expressing cells. Physiologically, we showed that decreases of both p27 mRNA and its protein expressions are well correlated to PCBP1 depletion in ovary, colon and renal tumor samples, independent of the p27 ubiquitin ligase Skp2 level. Correlation of PCBP1 with p27 is also found in the tamoxifen, doxorubincin and lapatinib resistant breast cancer cells of GEO database.ConclusionOur results thereby indicate that loss of PCBP1 expression firstly attenuates p27 expression at post-transcriptional level, and subsequently promotes carcinogenesis. PCBP1 could be used as a diagnostic marker to cancer patients.

Dataset Information

Rp58 and p27^kip1 coordinate cell cycle exit and neuronal migration within the embryonic mouse cerebral cortex.

Background

Findings

Conclusions

Publications

Rp58 and p27<sup>kip1</sup> coordinate cell cycle exit and neuronal migration within the embryonic mouse cerebral cortex.

Similar Datasets

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Dataset Information

Rp58 and p27kip1 coordinate cell cycle exit and neuronal migration within the embryonic mouse cerebral cortex.

Background

Findings

Conclusions

Publications

Rp58 and p27<sup>kip1</sup> coordinate cell cycle exit and neuronal migration within the embryonic mouse cerebral cortex.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Rp58 and p27^kip1 coordinate cell cycle exit and neuronal migration within the embryonic mouse cerebral cortex.