Asymmetric nuclear division of neural stem cells contributes to the formation of sibling nuclei with different identities
Preprint posted on 29 August 2020 https://www.biorxiv.org/content/10.1101/2020.08.29.272724v1
Article now published in Current Biology at http://dx.doi.org/10.1016/j.cub.2021.06.063
Asymmetric divisions are a central feature in cellular differentiation, enabling the generation of a diversity of cell types from an initially homogenous cell population (Knoblich, 2010). This plays a key role during early embryonic development, whereby a specific signal (for example, the sperm entry site in C. elegans embryos) can initiate polarity establishment, leading to the unequal distribution of polarized components between daughter cells in subsequent cell divisions (Gönczy, 2008). Indeed, this symmetry breaking event has been shown to differentially trigger cell fate specification pathways in various organisms (Ajduk and Zernicka-Goetz, 2016).
In the stem cell niche, asymmetric divisions also generate daughter cells with distinct identities – differentiated cells and self-renewing stem cells (Knoblich, 2010). This is exemplified in Drosophila neuroblasts, whereby asymmetric division produces a larger neuroblast on the apical side and a smaller basal ganglion mother cell (GMC). While this classical example of asymmetric cell division has been intensely studied, most have focused on the asymmetric inheritance of polarized transcription factors that activate distinct transcriptional programs directing cell fate. In this new preprint, Roubinet et al. reveal an additional function of nuclear asymmetries, and dissect the interplay between cell and nuclear divisions during the asymmetric divisions driving fate specification in Drosophila neuroblasts.
To characterize nuclear division dynamics during the asymmetric cell divisions of Drosophila neuroblasts, the authors performed live cell imaging of nuclear membrane and spindle markers during mitosis (Fig. 1). Unlike divisions occurring in mammalian cells where the nuclear envelope is disassembled and subsequently reformed at the end of mitosis (“open mitosis”), or mitotic events in other eukaryotes where an intact nuclear envelope is retained throughout division (“closed mitosis”), Drosophila neuroblasts follow a pattern of “semi-closed mitosis” – the nuclear compartment is retained throughout mitosis, but becomes permeable to cytoplasmic proteins with multiple perforations throughout the nuclear membranes. By the end of mitosis, the resultant neuroblasts and GMCs exhibit not only differences in cell volumes, but also distinct asymmetries in nuclear size and composition.
Figure 1. Nuclear membrane markers (green) and spindle marker (red) within two neuroblasts undergoing mitosis. Adapted from Figure 1B from Roubinet et al. 2020.
The retention of a nuclear envelope during “semi-closed” mitosis in this system necessitates a dynamic remodelling of the nuclear membrane during cell division to form two separate daughter nuclei of different sizes. Indeed, live cell imaging revealed formation of membrane extensions in the mitotic nuclear envelope, which ultimately enclosed individual daughter nuclei. Importantly, the authors find that the mitotic spindle defines the location of nuclear envelope resealing: the longer distance between the apical edge of the mitotic spindle and apical centrosome generates larger daughter nuclei in the apical neuroblasts, whereas the shorter distance between the basal mitotic spindle and basal centrosome produces smaller nuclei in basal GMCs. Strikingly, manipulations of spindle density and length to alter spindle asymmetries were able to induce corresponding changes in nuclear asymmetries. These results lend strong support to the role of mitotic spindle asymmetries in generating asymmetric nuclear envelope resealing and ultimately different daughter nuclei sizes.
Following nuclear envelope resealing, size asymmetry between daughter nuclei further increases. While nuclear size of GMCs rapidly stabilizes, neuroblast nuclei continue to grow before reaching their final nuclear size. The authors found that this nuclear growth differential could be attributed to the availability of ER membrane needed for nuclear envelope expansion to accommodate the nuclear size increase. Thus, a combination of asymmetric nuclear envelope resealing and differential nuclear growth regulates the nuclear size asymmetries between neuroblasts and GMCs.
What are the implications of asymmetric nuclear divisions? Firstly, differences in nuclear size can impose different physical constraints on packing and organization of chromatin, and the accumulation of epigenetic marks associated with stemness or neural differentiation. Secondly, the timing of asymmetric nuclear divisions appears to play a critical role – nuclear divisions are completed prior to the release of cortical proteins/fate determinants and their nuclear import, as well as the completion of cytokinesis. Crucially, cytokinetic failure led to cortical proteins being released into a common cytoplasmic pool, resulting in a loss of differential nuclear accumulation of fate determinants in daughter nuclei that is required to specify distinct daughter cell identities. Therefore, three factors are required in combination for the asymmetric division and generation of neuroblasts and GMCs: 1) asymmetric nuclear division, 2) cortical release of fate determinants, and 3) completion of cytokinesis.
What I like about this preprint
The authors use beautiful live cell imaging to uncover a novel role for asymmetric nuclear divisions in the specification of distinct cellular fates, during the asymmetric divisions producing neuroblasts and GMCs. Although important differences between the “semi-closed” form of mitosis in Drosophila neuroblasts and the “open” and “closed” models in other systems remain, this study presents a new perspective for understanding asymmetric divisions in general, by highlighting how nuclear size could impact chromatin organization and epigenetic differences driving differential fate specification in daughter cells. Indeed, others have identified asymmetries in histone inheritance during asymmetric cell divisions in Drosophila germline stem cells (Tran et al., 2012), but whether it is linked to nuclear size and/or composition remains to be investigated.
Questions for authors
- The authors describe differences in both nuclear size and composition between neuroblasts and GMCs – for example, nuclear membranes of neuroblasts display greater accumulation of nuclear pore complexes as compared to those in GMCs. While the nuclear size differences can be attributed to spindle asymmetries and availability of ER membrane, how do the asymmetries in nuclear membrane composition arise?
- Does altering nuclear asymmetry (via the spindle manipulations used in this study, or otherwise) induce differences in chromatin organization or acquisition of epigenetic markers?
- Ajduk, A., and Zernicka-Goetz, M. (2016). Polarity and cell division orientation in the cleavage embryo: from worm to human. Mol. Hum. Reprod. 22, 691–703.
- Gönczy, P. (2008). Mechanisms of asymmetric cell division: flies and worms pave the way. Nature Reviews Molecular Cell Biology 9, 355–366.
- Knoblich, J.A. (2010). Asymmetric cell division: recent developments and their implications for tumour biology. Nature Reviews Molecular Cell Biology 11, 849–860.
- Tran, V., Lim, C., Xie, J., and Chen, X. (2012). Asymmetric Division of Drosophila Male Germline Stem Cell Shows Asymmetric Histone Distribution. Science 338, 679–682.
Posted on: 3 September 2020Read preprint
Also in the cell biology category:
Invasion of glioma cells through confined space requires membrane tension regulation and mechano-electrical coupling via Plexin-B2
Excitable Rho dynamics drive cell contractions by sequentially inducing ERM protein-mediated actin-membrane attachment and actomyosin contractility
Nanos2+ cells give rise to germline and somatic lineages in the sea anemone Nematostella vectensis
preListscell biology category:in the
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
|Alex Eve, Katherine Brown
preLights peer support – preprints of interest
This is a preprint repository to organise the preprints and preLights covered through the 'preLights peer support' initiative.
|preLights peer support
The Society for Developmental Biology 82nd Annual Meeting
This preList is made up of the preprints discussed during the Society for Developmental Biology 82nd Annual Meeting that took place in Chicago in July 2023.
|Joyce Yu, Katherine Brown
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
Journal of Cell Science meeting ‘Imaging Cell Dynamics’
This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
|Sergio Menchero et al.
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
|Nadja Hümpfer et al.
The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
Planar Cell Polarity – PCP
This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.
BioMalPar XVI: Biology and Pathology of the Malaria Parasite
[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria
|Dey Lab, Samantha Seah
Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.
Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20
|Maiko Kitaoka et al.
A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.
|Paul Gerald L. Sanchez and Stefano Vianello
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
|Madhuja Samaddar et al.
EMBL Seeing is Believing – Imaging the Molecular Processes of Life
Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019
Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.
|Sandra Malmgren Hill
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.
|Pablo Ranea Robles
BSCB/BSDB Annual Meeting 2019
Preprints presented at the BSCB/BSDB Annual Meeting 2019
This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.
|Sandra Franco Iborra
Biophysical Society Annual Meeting 2019
Few of the preprints that were discussed in the recent BPS annual meeting at Baltimore, USA
|Joseph Jose Thottacherry
ASCB/EMBO Annual Meeting 2018
This list relates to preprints that were discussed at the recent ASCB conference.
|Dey Lab, Amanda Haage