Asymmetric inheritance of Cyclin D2 maintains proliferative neural stem/progenitor cells: A critical event in brain development and evolution

Tsunekawa, Yuji; Kikkawa, Takako; Osumi, Noriko

doi:10.1111/dgd.12135

Cited by 25 publications

(29 citation statements)

References 87 publications

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“…Given the ability of progenitor cells to proliferate as well, we found that many proliferative neuron-restricted progenitors were accompanied by fewer proliferative NSCs in neurospheres derived from sNSCs than from cNSCs. Additionally, the time required for the development of the cerebral cortex is markedly long compared with spinal cord development [38,39], and E12.5 is the time for the cerebral cortex to generate a large pool of NSCs for further expansion [14,40,41]. On the other hand, sNSCs presented in this study are committed to the production of progenitor cells.…”

Section: Discussionmentioning

confidence: 83%

Identification and Characterization of Secondary Neural Tube-Derived Embryonic Neural Stem Cells In Vitro

Shaker

Kim

et al. 2015

Stem Cells and Development

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Secondary neurulation is an embryonic progress that gives rise to the secondary neural tube, the precursor of the lower spinal cord region. The secondary neural tube is derived from aggregated Sox2-expressing neural cells at the dorsal region of the tail bud, which eventually forms rosette or tube-like structures to give rise to neural tissues in the tail bud. We addressed whether the embryonic tail contains neural stem cells (NSCs), namely secondary NSCs (sNSCs), with the potential for self-renewal in vitro. Using in vitro neurosphere assays, neurospheres readily formed at the rosette and neural-tube levels, but less frequently at the tail bud tip level. Furthermore, we identified that sNSC-generated neurospheres were significantly smaller in size compared with cortical neurospheres. Interestingly, various cell cycle analyses revealed that this difference was not due to a reduction in the proliferation rate of NSCs, but rather the neuronal commitment of sNSCs, as sNSC-derived neurospheres contain more committed neuronal progenitor cells, even in the presence of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). These results suggest that the higher tendency for sNSCs to spontaneously differentiate into progenitor cells may explain the limited expansion of the secondary neural tube during embryonic development.

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Section: Discussionmentioning

confidence: 83%

Identification and Characterization of Secondary Neural Tube-Derived Embryonic Neural Stem Cells In Vitro

Shaker

Kim

et al. 2015

Stem Cells and Development

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“…During development, local synthesis of cytoskeletal and signaling molecules would be particularly advantageous as the cortex undergoes radial expansion [46], necessitating remodeling and growth of RGC endfeet. Local translation of fate determinants also could impact progenitor symmetric and asymmetric divisions and specify distinct neuronal sub-types [18, 47]. Indeed, we discovered endfoot transcripts encoding nuclear factors, which could function locally or shuttle back to the cell body, as has been observed in neuronal axons [48, 49].…”

Section: Discussionmentioning

confidence: 99%

Dynamic mRNA Transport and Local Translation in Radial Glial Progenitors of the Developing Brain

et al. 2016

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SUMMARY In the developing brain, neurons are produced from neural stem cells termed radial glia [1, 2]. Radial glial progenitors span the neuroepithelium, extending long basal processes to form endfeet hundreds of micrometers away from the soma. Basal structures influence neuronal migration, tissue integrity, and proliferation [3–7]. Yet, despite the significance of these distal structures, their cell biology remains poorly characterized, impeding our understanding of how basal processes and endfeet influence neurogenesis. Here we use live imaging of embryonic brain tissue to visualize, for the first time, rapid mRNA transport in radial glia, revealing that the basal process is a highway for directed molecular transport. RNA- and mRNA-binding proteins, including the syndromic autism protein FMRP, move in basal processes at velocities consistent with microtubule-based transport, accumulating in endfeet. We develop an ex vivo tissue preparation to mechanically isolate radial glia endfeet from the soma, and we use photoconvertible proteins to demonstrate that mRNA is locally translated. Using RNA immunoprecipitation and microarray analyses of endfeet, we discover FMRP-bound transcripts, which encode signaling and cytoskeletal regulators, including many implicated in autism and neurogenesis. We show FMRP controls transport and localization of one target, Kif26a. These discoveries reveal a rich, regulated local transcriptome in radial glia, far from the soma, and establish a tractable mammalian model for studying mRNA transport and local translation in vivo. We conclude that cytoskeletal and signaling events at endfeet may be controlled through translation of specific mRNAs transported from the soma, exposing new mechanistic layers within stem cells of the developing brain.

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“…In addition, Cyclin D2 is asymmetrically distributed in daughter cells produced by radial glia cell proliferation in the developing cortex and has a role in G1/S progression. The daughter cell that receives Cyclin D2 maintains its radial glia proliferative state, whereas the other cell undergoes differentiation (reviewed in [44]). Finally, there is evidence that Cyclin D2 is required for the transition from radial glia to intermediate progenitor cells and has a role in proliferation and expansion of the intermediate progenitor pool [45].…”

Section: Discussionmentioning

confidence: 99%

Akirin2 is essential for the formation of the cerebral cortex

et al. 2016

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BackgroundThe proper spatial and temporal regulation of dorsal telencephalic progenitor behavior is a prerequisite for the formation of the highly-organized, six-layered cerebral cortex. Premature differentiation of cells, disruption of cell cycle timing, excessive apoptosis, and/or incorrect neuronal migration signals can have devastating effects, resulting in a number of neurodevelopmental disorders involving microcephaly and/or lissencephaly. Though genes encoding many key players in cortical development have been identified, our understanding remains incomplete. We show that the gene encoding Akirin2, a small nuclear protein, is expressed in the embryonic telencephalon. Converging evidence indicates that Akirin2 acts as a bridge between transcription factors (including Twist and NF-κB proteins) and the BAF (SWI/SNF) chromatin remodeling machinery to regulate patterns of gene expression. Constitutive knockout of Akirin2 is early embryonic lethal in mice, while restricted loss in B cells led to disrupted proliferation and cell survival.MethodsWe generated cortex-restricted Akirin2 knockouts by crossing mice harboring a floxed Akirin2 allele with the Emx1-Cre transgenic line and assessed the resulting embryos using in situ hybridization, EdU labeling, and immunohistochemistry.ResultsThe vast majority of Akirin2 mutants do not survive past birth, and exhibit extreme microcephaly, with little dorsal telencephalic tissue and no recognizable cortex. This is primarily due to massive cell death of early cortical progenitors, which begins at embryonic day (E)10, shortly after Emx1-Cre is active. Immunostaining and cell cycle analysis using EdU labeling indicate that Akirin2-null progenitors fail to proliferate normally, produce fewer neurons, and undergo extensive apoptosis. All of the neurons that are generated in Akirin2 mutants also undergo apoptosis by E12. In situ hybridization for Wnt3a and Wnt-responsive genes suggest defective formation and/or function of the cortical hem in Akirin2 null mice. Furthermore, the apical ventricular surface becomes disrupted, and Sox2-positive progenitors are found to “spill” into the lateral ventricle.ConclusionsOur data demonstrate a previously-unsuspected role for Akirin2 in early cortical development and, given its known nuclear roles, suggest that it may act to regulate gene expression patterns critical for early progenitor cell behavior and cortical neuron production.Electronic supplementary materialThe online version of this article (doi:10.1186/s13064-016-0076-8) contains supplementary material, which is available to authorized users.

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Asymmetric inheritance of Cyclin D2 maintains proliferative neural stem/progenitor cells: A critical event in brain development and evolution

Cited by 25 publications

References 87 publications

Identification and Characterization of Secondary Neural Tube-Derived Embryonic Neural Stem Cells In Vitro

Identification and Characterization of Secondary Neural Tube-Derived Embryonic Neural Stem Cells In Vitro

Dynamic mRNA Transport and Local Translation in Radial Glial Progenitors of the Developing Brain

Akirin2 is essential for the formation of the cerebral cortex

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