Asymmetric cell division: fly neuroblast meets worm zygote

doi:10.1016/S0955-0674(00)00176-9

Current Opinion in Cell Biology

Volume 13, Issue 1, 1 February 2001, Pages 68-75

https://doi.org/10.1016/S0955-0674(00)00176-9 Get rights and content

Abstract

Both Drosophila neuroblasts and Caenorhabditis elegans zygotes use a conserved protein complex to establish cell polarity and regulate spindle orientation. Mammalian epithelia also use this complex to regulate apical/basal polarity. Recent results have allowed us to compare the mechanisms regulating asymmetric cell division in Drosophila neuroblasts and the C. elegans zygote.

Introduction

Embryonic Drosophila neuroblasts (neuronal precursor cells) develop from an apical/basal polarized epithelium called the ventral neuroectoderm (Fig. 1). Individual neuroblasts move out of the epithelium and come to lie adjacent to the basal surface of the neuroectoderm, losing their epithelial morphology but retaining aspects of apical/basal polarity. Neuroblasts repeatedly divide asymmetrically along their apical/basal axis. These unequal divisions produce larger apical daughters that retain the stem-cell-like properties of a neuroblast and smaller, fate-committed basal daughter cells called ganglion mother cells (GMCs) that produce neurons or glia.

In another example of asymmetric cell division, the one-cell Caenorhabditis elegans embryo, called P₀, divides along its anterior–posterior (a–p) axis to produce a large anterior blastomere at the two-cell stage (AB) and a small posterior P₁ blastomere (Fig. 2). In addition to their unequal size, these two cells have different cell cycle times and are born committed to distinct fates [1], [2], [3]. AB generates predominantly ectodermal cell types, whereas P₁ generates mesoderm, endoderm and germline cells. P1 and its descendants undergo repeated asymmetric divisions that are largely responsible for patterning the early embryo [4], but we focus here on the first division of P₀.

In spite of the apparently substantial differences between a fly neuroblast and a one-cell worm embryo, recent work has revealed extensive parallels in the mechanisms regulating protein localization and spindle orientation during asymmetric cell divisions. Furthermore, vertebrate epithelia also use related mechanisms to establish or maintain apical/basal polarity. Previous reviews have covered earlier work on the asymmetric division of neuroblasts and early C. elegans blastomeres, as well as germ cell and post-embryonic asymmetric division in Drosophila and C. elegans [3], [5], [6], [7], [8]. Here we present recent results and highlight common features of cell polarity and asymmetric division in fly neuroblasts and the worm zygote.

Section snippets

Establishing cell polarity: a conserved apical/anterior protein complex in flies, worms and vertebrates

The initial apical/basal polarity of a Drosophila neuroblast is inherited, at least in part, from the epithelium that generates it. A newly delaminated neuroblast maintains apical enrichment of several proteins found at the apical cortex of epithelial cells. These proteins include the multi-PDZ (PSD-95/Discs large/ZO-1) domain protein Bazooka (Baz), the single-PDZ domain protein DmPAR-6 and an atypical protein kinase C, aPKC [9], [10], [11], [12, [13. These three proteins are conserved in C.

Functions of the apical/anterior protein complex

In Drosophila embryonic neuroblasts, the Baz, DmPar-6 and aPKC apical complex regulates basal protein localization and spindle orientation; in C. elegans zygotes, the PAR-3, PAR-6 and PKC-3 anterior complex has similar but distinct roles in posterior protein localization and spindle orientation. In the following two sections we discuss similarities and differences in how this evolutionarily conserved protein complex functions in the neuroblast and zygote.

Basal/posterior protein localization

Wild-type Drosophila neuroblasts have two protein complexes that are basally localized during mitosis: the ‘Miranda complex’ and the ‘Numb complex.’ The Miranda complex contains Miranda (a cortically associated coiled-coil domain protein), Prospero (a homeodomain-containing transcription factor that binds to Miranda and requires it for cortical association), Staufen (an RNA-binding protein that also binds to Miranda and requires it for cortical localization), and prospero mRNA (which requires

Spindle orientation

For reliable asymmetric cell division, the mitotic spindle must be aligned with the axis of cell polarization, which leads to the question of how this is accomplished in the neuroblast or zygote. In Drosophila, time-lapse imaging with a GFP-tagged MT-binding protein was used to show that the neuroblast spindle initially aligns perpendicular to the apical/basal axis, but then rotates 90° during metaphase to align with the apical/basal axis [40 radical dot ]. Spindle rotation is rapid and occurs after the

Spindle asymmetry and unequal cell division

In neuroblasts, the mitotic spindle becomes asymmetric soon after it aligns along the apical/basal axis. In both embryonic and larval neuroblasts, the basal centrosome and astral MTs disappear by late telophase [40 radical dot ]; this explains why larval GMCs, which inherit the basal spindle pole, divide with an asterless, centrosome-free spindle [44]. In addition, both embryonic and larval neuroblasts appear to have longer kinetochore MTs in the apical half of the spindle, thereby shifting the spindle

Microfilaments and the establishment of cell polarity

Drug studies first showed that MFs are essential for establishing a–p polarity in C. elegans [52]. More recently, further insight into the role that MFs play in establishing an a–p axis has come from an analysis of both NMY-2, a type II non-muscle myosin heavy chain that binds to PAR-1, and MLC-4, the non-muscle myosin regulatory light chain. If either NMY-2 or MLC-4 function is eliminated, many, but not all signs, of a–p polarity are lost [53], [54]. In particular, PAR-2 still localizes to the

Generation of cell diversity

The ultimate role of asymmetric cell division is to create two distinct cell types. How are the distinct neuroblast/GMC or AB/P₁ cell fates established? There are no cell fate determinants known to be localized to the neuroblast during asymmetric division: all apical proteins are degraded or delocalized before cleavage. In contrast, several cell fate determinants localize to the basal cortex of mitotic neuroblasts and segregate specifically into the GMC. The best characterized example is

Conclusions and future directions

Recent work has revealed a conserved apical/anterior protein complex that regulates cell polarity in Drosophila neuroblasts, Drosophila epithelia, mammalian epithelia and C. elegans zygotes. Different proteins are known to interact with this protein complex in each cell-type, and this may allow a common cell polarity system to regulate cell-type-specific properties such as maintaining different membrane domains in epithelia or regulating spindle orientation and the generation of cell diversity

Update

Recent work reveals a role for the tumor suppressor genes lgl and dlg in establishing a neuroblast cell polarity. Although they function in epithelial cells to restrict proteins to the apical membrane domain [20 radical dot ], in neuroblasts they are required to restrict proteins such as Miranda, Prospero and Pon to the basal cortex. These proteins relocate uniformly around the cortex or onto the mitotic spindle and centrosomes in the absence of lgl or dlg function [59, [60.

Acknowledgements

We thank Ken Kemphues at Cornell University for sharing ideas and information, and Ken Kemphues, Rebecca Lyczak, Aaron Severson, and Karsten Siller for comments on the manuscript.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

of special interest
of outstanding interest

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ReviewAsymmetric cell division: fly neuroblast meets worm zygote

Abstract

Introduction

Section snippets

Establishing cell polarity: a conserved apical/anterior protein complex in flies, worms and vertebrates

Functions of the apical/anterior protein complex

Basal/posterior protein localization

Spindle orientation

Spindle asymmetry and unequal cell division

Microfilaments and the establishment of cell polarity

Generation of cell diversity

Conclusions and future directions

Update

Acknowledgements

References and recommended reading

Dev Biol

Cell

Curr Opin Genet Dev

Dev Biol

Cell

Curr Opin Cell Biol

Curr Opin Neurobiol

Curr Biol

Mech Dev

Curr Biol

Curr Biol

Curr Biol

Cell

Curr Biol

Dev Biol

Cell

Cell

Cell

Cell

Dev Biol

Mol Cell

Curr Biol

Asymmetric cell division: from A to Z

Genes Dev

Bazooka recruits Inscuteable to orient asymmetric cell divisions in Drosophila neuroblasts

Nature

Bazooka provides an apical cue for Inscuteable localization in Drosophila neuroblasts

Nature

Drosophila atypical protein kinase C associates with Bazooka and controls polarity of epithelia and neuroblasts

J Cell Biol

Meiotic maturation induces animal-vegetal asymmetric distribution of aPKC and ASIP/PAR-3 in Xenopus oocytes

Development

The cell-polarity protein Par6 links Par3 and atypical protein kinase C to Cdc42

Nat Cell Biol

The mammalian homologue of the Caenorhabditis elegans polarity protein PAR-6 is a binding partner for the Rho GTPases Cdc42 and Rac1

J Cell Sci

Review
Asymmetric cell division: fly neuroblast meets worm zygote