Asymmetric Cell Division in Drosophila Neuroblasts

Abstract

Neuronal diversity provides the basis for brain complexity. Asymmetric division of neural stem cells is a fundamental strategy for generating such diversity. Drosophila neural stem cells called neuroblasts emerge as a key model for in‐depth understanding of asymmetric division. Asymmetric division of neuroblasts is regulated by a group of highly conserved intrinsic factors through three critical steps: establishment of cortical polarity, mitotic spindle orientation and asymmetric localisation/segregation of cell fate determinants. With each round of asymmetric division, a neuroblast generates a new neuroblast to self‐renew and a ganglion mother cell (GMC) that divides terminally giving rise to two neurons. In addition, neuroblasts acquire different temporal identities that contribute to the differential neurons subtypes generated.

Key Concepts

  • Asymmetric cell division is regulated by intrinsic machinery.
  • Par complex establishes cortical polarity of neuroblasts.
  • Pins–Gαi complex regulates spindle orientation.
  • Basal cell fate determinants promote neuronal differentiation.
  • Cell cycle regulators regulate asymmetric division of neuroblasts.
  • Positioning of cleavage furrow is regulated by two temporally independent pathways.
  • Temporal regulation of neuroblasts generates neuronal diversity.

Keywords: neuroblasts; asymmetric cell division; cortical polarity; spindle orientation; asymmetric segregation; temporal regulation; cell cycle regulators; cleavage furrow

Figure 1. Intrinsic regulation of neuroblast asymmetric division. Apical (green) and basal (red) proteins are asymmetrically localised at the cortex of mitotic neuroblasts. The Par complex, which comprises Baz, Par‐6 and aPKC, establishes cell polarity. Several proteins including PP2A, AurA, Lgl, Cdc42, Zif, Dap160 and Clueless (Clu) regulate the Par complex. The Gαi–Pins–Loco complex, which is linked through Insc to the Par complex, regulates mitotic spindle orientation either through Dlg–Khc73 complex or Mud. In addition, apical localisation of Mud is regulated by Gαi–Pins complex and Ctp–Ana2 complex. Basally localised Mira–Pros–Brat complex and Pon–Numb complex regulate differentiation in ganglion mother cell independent of each other. Basal localisation of Numb and Mira is regulated through direct phosphorylation by aPKC and/or indirectly through aPKC‐mediated phosphorylation of Lgl. Localisation of Mira is also regulated by PP4 subunit Flfl while Polo and PP2A regulate Numb localisation either directly or indirectly through Pon. Actomyosin‐dependent pathway (through Zip and Jar) also partially regulates localisation of basal complexes.
Figure 2. Type I and type II neuroblast lineages in Drosophila larval brain. Larval brain is composed of two brain hemispheres and a ventral nerve cord (VNC). Each brain hemisphere contains an optic lobe region that develops into the adult fly visual system and a central brain region where type I and type II neuroblasts lineages reside. Type I neuroblasts undergo asymmetric division to self‐renew and to generate a smaller daughter cell known as ganglion mother cell (GMC) that undergoes a terminal division to form two neurons/glia. On the other hand, with each asymmetric division, a type II neuroblast generates a new neuroblast and an intermediate neural progenitor (INP). Newly formed INPs are immature and will undergo a maturation process characterised by the gain of Asense (Ase). In mature form, INPs possess limited proliferative ability and can undergo 8–10 rounds of asymmetric division to self‐renew and generate GMCs that give rise to neurons/glia.
Figure 3. Temporal regulation of neuroblasts. (a) Temporal patterning of VNC neuroblasts. A series of transcription factors regulates the identity of neuroblasts and their neural progeny. NBs express different transcription factors at different temporal point that are inherited by the GMCs and neurons. Embryonic NBs consecutively express Hunchback (HB, yellow), Seven up (Svp, orange), Kruppel (Kr, blue), Pdm1/2 (Pdm, red) and lastly, Castor (Cas, green) before entering quiescence. At larval stage, NBs resume Cas expression but transit to Svp expression shortly after. Transition to Svp induces transition from large Chinmo expressing neurons to small Broad complex (Br–C) expressing neurons. However, temporal transcription factors expressed after Svp in larval and pupal stage have yet been identified. (b) Temporal patterning of DM2‐3 type II neuroblasts. (1) Neuroblast temporal cascade. DM1‐3 type II neuroblasts express Diachete (D) and Castor (cas) at 24 h after larval hatching (ALH), while Svp is transiently expressed at 48 h ALH. Temporal factor express at later stage is unknown. (2) INP temporal cascade. In addition, INPs generated from DM2‐6 type II neuroblasts also exhibit temporal patterning. INPs sequentially express D, Grainyhead (Grh) and Eyeless (Ey) over time. Ey+ old INPs generate from early D+/Cas+ neuroblasts produce either Repo+ (Reverse polarity) glia or Toy+ (Twin of eyeless) neurons. Late neuroblasts derived D+ young INPs produce D+ or Bsh+ (Brain‐specific homeobox) progenies.
Figure 4. Implications of asymmetric cell division with cancer formation. (a) A wild‐type neuroblast undergoes asymmetric division to self‐renewal and to generate a GMC that gives rise two neurons/glia. (b) Altered asymmetric proteins segregation, for instance by loss of aurora‐A, can generate two neuroblast‐like daughter cells with self‐renewing ability, leading to neuroblast overgrowth. (c) Spindle misorientation can cause missegregation of asymmetrically localised proteins, resulting in neuroblasts overgrowth.
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Further Reading

Kohwi M and Doe CQ (2013) Temporal fate specification and neural progenitor competence during development. Nature Reviews Neuroscience 14 (12): 823–838.

Peyre E and Morin X (2012) An oblique view on the role of spindle orientation in vertebrate neurogenesis. Development, Growth & Differentiation 54 (3): 287–305. DOI: 10.1111/j.1440-169X.2012.01350.x.

Taverna E , Gotz M and Huttner WB (2014) The cell biology of neurogenesis: toward an understanding of the development and evolution of the neocortex. Annual Review of Cell and Developmental Biology 30: 465–502.

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Koe, Chwee Tat, and Wang, Hongyan(Mar 2016) Asymmetric Cell Division in Drosophila Neuroblasts. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020861]