ReviewAsymmetric division of Drosophila neural stem cells: a basis for neural diversity
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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Cited by (57)
NUMB-ing down cancer by more than just a NOTCH
2011, Biochimica et Biophysica Acta - Reviews on CancerCitation Excerpt :As discussed above, initial evidence argued in favor of the idea that the asymmetric partitioning of the Numb:α-adaptin complex in the pIIb cell might cause selective endocytosis of Notch (presumably resulting in its degradation) in this cell [50]. This hypothesis, however, presented some inherent difficulties: i) the plasma membrane levels of Notch are similar in pIIa and pIIb cells, in contradiction with the hypothesis that reduced Notch levels in the pIIb cell would create the necessary asymmetry for directional signaling pIIb –> pIIa; ii) Notch is involved in many developmental decisions in the fly, and cells undergoing these decisions co-express Numb and Notch [73,74]. So why does Numb inhibit Notch signaling (or cause its endocytosis) only during ACD [2,75–78]?
Cell cycle independent role of Cyclin E during neural cell fate specification in Drosophila is mediated by its regulation of Prospero function
2010, Developmental BiologyCitation Excerpt :Cortical localization of Pros is mediated by the anchoring protein Miranda (Mira), which is itself localized at the basal cortex of dividing neuroblasts and segregated into the ganglion mother cells, where it disappears soon in contrast to Pros. As indicated by mutant analysis Mira performs two distinct functions: (1) asymmetric localization and partition of Pros during NB mitosis, and (2) subsequent release of Pros in the ganglion mother cell (Ikeshima-Kataoka et al., 1997; Matsuzaki, 2000; Matsuzaki et al., 1998; Shen et al., 1997). The miraRR127 mutant allele affects only one of these functions: MiraRR127 protein can bind to but cannot release Pros, which therefore persists at the cell cortex (Ikeshima-Kataoka et al., 1997).
Two forms of human Inscuteable-related protein that links Par3 to the Pins homologues LGN and AGS3
2006, Biochemical and Biophysical Research CommunicationsCitation Excerpt :This seems to be consistent with the finding that the two forms result from the alternative use of the first exons 1a and 1b (Fig. 2), upstream of which distinct promoters may be located. In Drosophila neuroblasts, Insc associates with both Pins and Bazooka to regulate cell polarity for asymmetric division [5–9]. We tested the ability of human Insc proteins to interact with the human Pins homologues LGN and AGS3.
Early Embryonic Development: Neurogenesis (CNS)
2005, Comprehensive Molecular Insect ScienceFormation of the brain by stem cell divisions of large neuroblasts in Oikopleura dioica, a simple chordate
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