Review
Asymmetric division of Drosophila neural stem cells: a basis for neural diversity

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Abstract

Recent studies of Drosophila neural precursor cells have unveiled the essential roles played by asymmetric cell divisions in the determination of cell fates during neural development. Our understanding now extends to the molecular nature of the cell polarity that underlies asymmetric divisions. This polarity is conserved among neural stem cells, epithelial cells and fertilized eggs.

Introduction

During neural development, a great many neurons arise from a small population of neural precursor cells, and these neurons establish individual identities. Studies of Drosophila melanogaster have revealed that asymmetric cell divisions of neural precursor cells play crucial roles in specifying neural cell types and neuronal identities (see 1, 2, 3, 4 for reviews). In this review, I will summarize our present knowledge of these asymmetric divisions of Drosophila neural precursor cells, and discuss the cell polarity that regulates asymmetric divisions.

Section snippets

Asymmetric division of neural precursor cells

Neural stem-like cells in the Drosophila central nervous system (CNS) are neuroblasts that delaminate from the neuroectoderm [5]. Each neuroblast has a unique cell division pattern through which to generate a unique set of neurons and/or glia, depending on its individual identity 6, 7, 8, 9. Typical neuroblasts divide perpendicularly to the neuroepithelial layer to produce another neuroblast and a smaller ganglion mother cell (GMC) (Figure 1a). While neuroblasts undergo this type of asymmetric

Asymmetric partition of cell fate determinants

The investigation of asymmetric divisions in Drosophila neural precursors has been accelerated by the discovery of the asymmetric segregation of two key proteins 11, 12, 13, 14. These key proteins are the transcription factor Prospero 15, 16, 17 and the cortical protein Numb that antagonizes Notch signaling [18]. Both Numb and Prospero are synthesized in neuroblasts and segregated asymmetrically into the GMC during divisions (Figure 1).

The first protein that was discovered to be asymmetrically

Localizing factors of cell fate determinants

Asymmetric segregation of Prospero and Numb into just one of the neuroblast daughter cells occurs by virtue of their asymmetric localization — they are localised in a crescent-shape at the basal cell cortex where the GMC buds off 12, 13, 14, 15. Localization of Prospero is determined by an anchoring protein Miranda, which has been identified as the factor that binds to a domain in Prospero that is responsible for its asymmetric localization 29, 30. Miranda is itself localized at the basal

Asymmetric segregation of mRNA

Several mRNAs for cell fate determinants are also unequally segregated to one daughter cell during neuroblast division 32••, 33••, 34••. prospero mRNA is associated with a double-strand RNA-binding protein known as Staufen at mitosis [32••]; both are asymmetrically localized to the basal cortex of neuroblasts (Figure 2) [33••]. It turned out that Miranda localizes this prospero mRNA/Staufen complex by binding Staufen 35•, 36•, 37•, 38•. Whereas Miranda thus plays a role in the asymmetric

Orientation of the mitotic spindle

Asymmetric localization of cell fate determinants in dividing cells is not the sole prerequisite for their asymmetric segregation into one daughter cell: it is also essential for the mitotic spindle to orient parallel to the polar distribution of determinants. Inscuteable protein [43] is responsible for this coordination between the orientation of the spindle and the axis of protein localization [44]. Inscuteable is not expressed in the neuroepithelial cell layer; it is first detectable at the

Cell polarity in neuroblasts and epithelial cells

The distribution of cell fate determinants in neuroblasts changes dynamically during the cell cycle (Figure 2). Miranda, Prospero and Staufen are colocalized with Inscuteable at the apical cortex during late interphase 14, 35•, 38•; physical interaction between Inscuteable and Miranda may account, in part, for this colocalization at the apical pole [35]. Upon mitosis, these proteins are sorted to the opposite side of the cell cortex and disappear from the neuroblast when they are incorporated

The role of Bazooka in organizing cell polarity

In epithelial cells, adhesive structures such as adherence junctions act together with the underlying cortical cytoskeleton to maintain the apical–basal polarity [48]. A difference between epithelial cells and neuroblasts is that neuroblasts appear to lack the apical junctional complexes that are important in maintaining the apical–basal polarity in epithelia. This leads to the hypothesis that there is an intrinsic center for the organization of intracellular asymmetry in neuroblasts [12].

A conserved mechanism for intracellular asymmetry

Proteins homologous to Drosophila Bazooka have been identified in the nematode C. elegans and in vertebrates. The vertebrate homolog has been identified as a binding protein of an atypical protein kinase C (ASIP, or atypical PKC isotype-specific interacting protein) [53]. The nematode homolog is encoded by the par-3 gene [54], one of six par loci that are required in early asymmetric cleavages of fertilized eggs [55]. During such early cleavages in C. elegans, the PAR-3 protein and the atypical

Conclusions

Beginning with asymmetric segregation of cell fate determinants, studies on asymmetric fate decisions in neural cells have advanced over the past few years to include the identification of several proteins regulating the localization of the molecular determinants, the orientation of the spindle, and, most recently, the recognition of an evolutionarily conserved cell-polarity organizer. In spite of this rapid progress, many important questions remain unanswered. How does apically localized

Acknowledgements

I thank Eli Knust and Juergen Knoblich for communicating manuscripts prior to publication. I also thank Chris Doe, Juergen Knoblich, Eli Knust, William Chia, Angela Giangrande, Atsuko Fujisawa-Sehara and the members of my lab for their helpful discussions and 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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