Specific polar subpopulations of astral microtubules control spindle orientation and symmetric neural stem cell division

Mora-Bermúdez, Felipe; Matsuzaki, Fumio; Huttner, Wieland B.

doi:10.7554/elife.02875

Cited by 52 publications

(68 citation statements)

References 64 publications

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“…Importantly, this differential behavior already exists in HeLa cells without plasmid DNA. This might be due to the old centriole nucleating more astral microtubules (19) and the amount of a specific subgroup of astral microtubules required for asymmetric stem cell divisions (18,30). Last but most importantly, we found the plasmid cluster to be relatively immobile during mitosis, which is a prerequisite for differential centrosome movement to bias the partition of the DNA clusters together with the young centrosome.…”

Section: Discussionmentioning

confidence: 72%

Asymmetric partitioning of transfected DNA during mammalian cell division

Wang

Denoth-Lippuner

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Foreign DNA molecules and chromosomal fragments are generally eliminated from proliferating cells, but we know little about how mammalian cells prevent their propagation. Here, we show that dividing human and canine cells partition transfected plasmid DNA asymmetrically, preferentially into the daughter cell harboring the young centrosome. Independently of how they entered the cell, most plasmids clustered in the cytoplasm. Unlike polystyrene beads of similar size, these clusters remained relatively immobile and physically associated to endoplasmic reticulum-derived membranes, as revealed by live cell and electron microscopy imaging. At entry of mitosis, most clusters localized near the centrosomes. As the two centrosomes split to assemble the bipolar spindle, predominantly the old centrosome migrated away, biasing the partition of the plasmid cluster toward the young centrosome. Down-regulation of the centrosomal proteins Ninein and adenomatous polyposis coli abolished this bias. Thus, we suggest that DNA clustering, cluster immobilization through association to the endoplasmic reticulum membrane, initial proximity between the cluster and centrosomes, and subsequent differential behavior of the two centrosomes together bias the partition of plasmid DNA during mitosis. This process leads to their progressive elimination from the proliferating population and might apply to any kind of foreign DNA molecule in mammalian cells. Furthermore, the functional difference of the centrosomes might also promote the asymmetric partitioning of other cellular components in other mammalian and possibly stem cells.foreign DNA | asymmetric cell division | centrosome | endoplasmic reticulum | Ninein G enerally, noncentromeric DNA molecules are mitotically instable in eukaryotes. This results in their apparent disappearance from an ever-increasing proportion of the progeny of an affected cell (e.g., 1-3). Endogenous sources of such DNA are recombination byproducts [double minutes, extrachromosomal ribosomal (r)DNA circles (ERCs) and other DNA circles (3-6)] or mitotic defects generating noncentromeric chromosomal fragments and cytoplasmic micronuclei (1, 7). Exogenous sources are DNA of pathogens or DNA, typically plasmids, artificially introduced into cells. For the latter, decades of work established that plasmid-born protein expression is transient, persisting only for a few cell cycles (8). This finding is consistent with plasmid DNA being somehow eliminated through divisions. Thus, some mechanisms seem to prevent the propagation of foreign DNA and extrachromosomal DNA in proliferating eukaryotic cells. However, how this is achieved is unclear.In animal cells, DNA sensors mediate the early detection of exogenous DNA, such as DNA of invading pathogens and artificially introduced DNA (9-11). Both in leukocytes and nonprofessional immune cells, these can trigger innate immune responses, such as cytokine production, autophagy, and apoptosis (9). However, what happens to the DNA molecules themselves over time is unclear. When microi...

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Section: Discussionmentioning

confidence: 72%

Asymmetric partitioning of transfected DNA during mammalian cell division

Wang

Denoth-Lippuner

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…We used an established live imaging method (Mora-Bermudez et al, 2014) to compare dividing cortical APs, i.e. cells undergoing mitosis at the ventricular surface (presumably mostly aRG), in slice cultures of both 11–13 wpc human fetal neocortex and human D30 cerebral organoids.…”

Section: Resultsmentioning

confidence: 99%

“…Spindle orientation can determine symmetric vs. asymmetric NSPC division (Lancaster and Knoblich, 2012; Mora-Bermudez and Huttner, 2015; Mora-Bermudez et al, 2014; Shitamukai and Matsuzaki, 2012) and is therefore a major candidate mechanism to explain the approximately 3-fold expansion of the neocortex in humans compared to great apes. We compared spindle orientation dynamics between human and chimpanzee APs in cerebral organoids.…”

Section: Resultsmentioning

confidence: 99%

“…Studies dissecting the switch between NSPC proliferation and differentiation have demonstrated that a central aspect of the cell division process, the orientation of the mitotic spindle, has a pivotal role, particularly in the case of APs (Lancaster and Knoblich, 2012; Mora-Bermudez and Huttner, 2015; Mora-Bermudez et al, 2014; Shitamukai and Matsuzaki, 2012). The orientation of the spindle relative to the apical-basal axis of cell polarity in mitotic apical radial glia, the major cortical neural stem cells (Götz and Huttner, 2005; Kriegstein and Alvarez-Buylla, 2009), can determine whether their division is symmetric or asymmetric, and whether it is proliferative or neurogenic, with regard to their progeny (Lancaster and Knoblich, 2012; Mora-Bermudez and Huttner, 2015; Mora-Bermudez et al, 2014; Shitamukai and Matsuzaki, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…The orientation of the spindle relative to the apical-basal axis of cell polarity in mitotic apical radial glia, the major cortical neural stem cells (Götz and Huttner, 2005; Kriegstein and Alvarez-Buylla, 2009), can determine whether their division is symmetric or asymmetric, and whether it is proliferative or neurogenic, with regard to their progeny (Lancaster and Knoblich, 2012; Mora-Bermudez and Huttner, 2015; Mora-Bermudez et al, 2014; Shitamukai and Matsuzaki, 2012). Comparing spindle orientation in mitotic APs may therefore provide insight into the cell biological basis underlying the differences between humans and chimpanzees in NSPC proliferation versus differentiation during neocortex development.…”

Section: Introductionmentioning

confidence: 99%

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Differences and similarities between human and chimpanzee neural progenitors during cerebral cortex development

Mora-Bermúdez

Badsha

Kanton

et al. 2016

eLife

Self Cite

216

212

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Human neocortex expansion likely contributed to the remarkable cognitive abilities of humans. This expansion is thought to primarily reflect differences in proliferation versus differentiation of neural progenitors during cortical development. Here, we have searched for such differences by analysing cerebral organoids from human and chimpanzees using immunohistofluorescence, live imaging, and single-cell transcriptomics. We find that the cytoarchitecture, cell type composition, and neurogenic gene expression programs of humans and chimpanzees are remarkably similar. Notably, however, live imaging of apical progenitor mitosis uncovered a lengthening of prometaphase-metaphase in humans compared to chimpanzees that is specific to proliferating progenitors and not observed in non-neural cells. Consistent with this, the small set of genes more highly expressed in human apical progenitors points to increased proliferative capacity, and the proportion of neurogenic basal progenitors is lower in humans. These subtle differences in cortical progenitors between humans and chimpanzees may have consequences for human neocortex evolution.DOI: http://dx.doi.org/10.7554/eLife.18683.001

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Vertebrate Neurogenesis: Cell Polarity

Zolessi

2016

Encyclopedia of Life Sciences

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Neurons originate from epithelial cells that, after proliferation and cell fate decisions, undergo a series of polarity transitions to achieve the differentiated state. The fate of neural progenitors depends on the interplay between cell cycle and neuroepithelial polarity by two main mechanisms: (1) asymmetric inheritance of cytoplasmic determinants, such as molecules of the apical adhesion complexes, and (2) interkinetic nuclear migration through gradients of signalling molecules such as Notch. Regarding cell fate, divisions can be symmetric or asymmetric. After a neuron is born, differentiation initiates with a downregulation of epithelial polarity, followed by cell detachment and migration, and the final acquisition of a neuronal morphology. All these transitions are based on extremely conserved molecular mechanisms, including the involvement of polarity protein complexes (such as the PAR3 complex) and small GTPases that mostly affect actin and microtubule dynamics. However, some important variations have been observed in different neuronal types and experimental conditions. Key Concepts Neurons are highly polarised cells that are generated from progenitors with a different kind of polarity: neuroepithelial cells. The neuroepithelium is an embryonic tissue characterised by its pseudo‐stratified organisation, with a basal lamina, sub‐apical cadherin‐based adhesion complexes and an apical primary cilium. The pseudo‐stratified organisation of the neuroepithelium is actively maintained by interkinetic nuclear migration, a process by which cell nuclei locate at different apicobasal positions, according to their stage in the cell cycle. Interkinetic nuclear migration provides the neuroepithelium with the possibility of rapidly proliferating while maintaining a relatively reduced size in the embryo. Neuroepithelial polarity and interkinetic nuclear migration favour the asymmetric distribution of signalling cues (including extracellular molecules and cytoplasmic determinants), which are essential for neurogenesis, neuronal migration and neuronal polarisation. Neurons are post‐mitotic cells, which are born from a progenitor cell division that can be symmetric (generating two neurons) or asymmetric (generating one neuron and another progenitor cell). After the last cell division close to the apical surface, neuroblasts must migrate to their final differentiation position, and this migration is also influenced by cell polarity cues. Neuronal polarisation mechanisms have largely been studied using cell cultures, where neurons extend an axon after a period of radially symmetric, multipolar organisation. In the living tissue neurons must not only polarise (form one axon and oppositely directed dendrites) but also orient properly (the axon and dendrite must be directed to the right orientation). In vitro , mechanisms of neuronal polarisation rely mostly on intrinsic signals, such as the asymmetric accumulation of the PAR3 complex; in vivo , however, these intrinsic molecules are modulated by extrinsic signals such as Laminin‐1 or N‐Cadherin.

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Specific polar subpopulations of astral microtubules control spindle orientation and symmetric neural stem cell division

Cited by 52 publications

References 64 publications

Asymmetric partitioning of transfected DNA during mammalian cell division

Asymmetric partitioning of transfected DNA during mammalian cell division

Differences and similarities between human and chimpanzee neural progenitors during cerebral cortex development

Vertebrate Neurogenesis: Cell Polarity

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