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• W2060976363 abstract "Developmental biologists at the turn of the century were the first to observe that mitotic spindle orientation and cell fates can be remarkably stereotyped during embryogenesis. This led to the proposal that reliable localization of intracellular “cell fate determinants” could produce the diversity of cells and tissues arising during embryogenesis. Recently, a number of RNAs and proteins that act as localized determinants have been identified, but we are still ignorant about how asymmetric localization and spindle orientation are coordinated. In this minireview, I will highlight the results of 10Kraut R. Chia W. Jan L.Y. Jan Y.N. Knoblich J.A. Nature. 1996; 383: 50-55Crossref PubMed Scopus (313) Google Scholar, who show that the Inscuteable protein controls both spindle orientation and asymmetric localization of two cell fate determinants in the Drosophila central nervous system (CNS). The Drosophila ectoderm is a polarized epithelium containing apically positioned adherens junctions, centrosomes, proteins, and RNAs (reviewed by8Knust E. Trends Genet. 1994; 10: 275-280Abstract Full Text PDF PubMed Scopus (21) Google Scholar, 4Eaton S. Simons K. Cell. 1995; 82: 5-8Abstract Full Text PDF PubMed Scopus (164) Google Scholar). It gives rise to three cell types, each with a characteristic mitotic spindle orientation (Figure 1). (1) Most superficial ectoderm produces epidermis. During mitosis, the centrosomes split and both migrate 90° basally to establish a spindle parallel (or “horizontal”) to the ectodermal surface, followed by a symmetric division in the plane of the ectoderm (1Callaini G. Anselmi F. Exp. Cell Res. 1988; 178: 415-425Crossref PubMed Scopus (19) Google Scholar). (2) Segmental CNS precursors (neuroblasts) delaminate into the embryo from the ventral ectoderm. During neuroblast mitosis, one centrosome remains apical and the other migrates 180° to the basal cortex, leading to a mitosis perpendicular (or “vertical”) to the surface of the embryo (13Spana E. Doe C.Q. Development. 1995; 121: 3187-3195PubMed Google Scholar). Neuroblast divisions are asymmetric: the basal sibling (ganglion mother cell; GMC) is smaller than the apical sibling (neuroblast), and each expresses a different set of genes. (3) The procephalic ectoderm produces the larval brain (2Campos-Ortega, J.A., and Hartenstein, V. (1985). The embryonic development of Drosophila melanogaster. (Berlin: Springer-Verlag).Google Scholar). These cells remain in the ectoderm layer as they enter mitosis; initially the spindle is parallel to the ectodermal surface, but prior to metaphase the spindle rotates 90° leading to a perpendicular division (10Kraut R. Chia W. Jan L.Y. Jan Y.N. Knoblich J.A. Nature. 1996; 383: 50-55Crossref PubMed Scopus (313) Google Scholar). Like ventral neuroblasts, the procephalic cells divide asymmetrically with a smaller basal sibling and larger apical sibling. inscuteable was first identified by 9Kraut R. Campos-Ortega J.A. Dev. Biol. 1996; 174: 65-81Crossref PubMed Scopus (148) Google Scholar, who showed that inscuteable is expressed in most CNS and sensory neural precursors, encodes a protein with predicted ankyrin and SH3 domains, and is required for normal nervous system development. The recent work of 10Kraut R. Chia W. Jan L.Y. Jan Y.N. Knoblich J.A. Nature. 1996; 383: 50-55Crossref PubMed Scopus (313) Google Scholar shows that the Inscuteable protein is asymmetrically localized to the apical cortex of vertically dividing cells (procephalic ectoderm and ventral neuroblasts) and is not present in horizontally dividing ectodermal cells (Figure 1). Inscuteable is apically localized during prophase and metaphase; by anaphase it is delocalized and/or degraded, and it is not segregated to either daughter cell. During subsequent neuroblast cell cycles, Inscuteable is detected at the apical cortex only during prophase and metaphase. Thus, Inscuteable protein is transiently localized to the apical cortex in all vertically dividing cells (procephalic ectoderm and neuroblasts) but not in horizontally dividing cells (ectoderm). 10Kraut R. Chia W. Jan L.Y. Jan Y.N. Knoblich J.A. Nature. 1996; 383: 50-55Crossref PubMed Scopus (313) Google Scholar show that Inscuteable localization is not only correlated with vertical spindle orientation, but that it is necessary and sufficient for establishing vertical spindle orientation (Figure 2). Embryos lacking Inscuteable do not reorient the spindle from horizontal to vertical in the procephalic ectoderm, and have a randomized spindle axis in ventral neuroblasts. Conversely, misexpression of Inscuteable in ectodermal cells results in apical localization of the Inscuteable protein and a vertical spindle orientation. Thus, apical Inscuteable is sufficient to trigger a vertical spindle axis in ectodermal cells that otherwise divide horizontally. It is unknown how apical Inscuteable protein establishes vertical spindle orientation, but it is tempting to speculate that it involves anchoring of one centrosome at the apical cortex. This is consistent with the transient localization of Inscuteable during centrosome migration or reorientation, and with its predicted ankyrin/SH3 domains that might mediate cytoskeletal attachment. In addition to controlling spindle orientation, Inscuteable is required for the normal localization of two cell fate determinants, Prospero and Numb (Figure 1). Numb was initially identified as a gene controlling binary cell fates in sensory organ cell lineages (16Uemura T. Sheperd S. Ackerman L. Jan L.Y. Jan Y.N. Cell. 1989; 58: 349-360Abstract Full Text PDF PubMed Scopus (391) Google Scholar). Prospero and Numb proteins are asymmetrically localized to the basal cortex of neuroblasts and specifically segregated into the GMC at mitosis (12Rhyu M.S. Jan L.Y. Jan Y.N. Cell. 1994; 76: 477-491Abstract Full Text PDF PubMed Scopus (612) Google Scholar, 6Hirata J. Nakagoshi H. Nabeshima Y. Matsuzaki F. Nature. 1995; 377: 627-630Crossref PubMed Scopus (290) Google Scholar, 7Knoblich J.A. Jan L.Y. Jan Y.N. Nature. 1995; 377: 624-627Crossref PubMed Scopus (407) Google Scholar, 15Spana E.P. Kopczynski C. Goodman C.S. Doe C.Q. Development. 1995; 121: 3489-3494Crossref PubMed Google Scholar). Prospero is a transcription factor that controls GMC-specific gene expression (13Spana E. Doe C.Q. Development. 1995; 121: 3187-3195PubMed Google Scholar). numb encodes a membrane-associated protein that is necessary and sufficient to specify the basal daughter cell fate in the MP2 CNS precursor (15Spana E.P. Kopczynski C. Goodman C.S. Doe C.Q. Development. 1995; 121: 3489-3494Crossref PubMed Google Scholar); recently Numb has been shown to control cell fate in both the CNS and the peripheral nervous system by binding to the intracellular domain of the Notch receptor and inhibiting Notch-mediated signal transduction (5Guo M. Jan L.Y. Jan Y.N. Neuron. 1996; 17 (in press)Abstract Full Text Full Text PDF PubMed Scopus (534) Google Scholar, 14Spana E.P. Doe C.Q. Neuron. 1996; 17: 21-26Abstract Full Text Full Text PDF PubMed Scopus (347) Google Scholar). Thus, both Prospero and Numb are asymmetrically localized determinants that control cell fate. In embryos lacking Inscuteable, all mitotic procephalic ectodermal cells show uniform cortical distribution of Prospero and Numb; ventral neuroblasts show either uniform distribution (24%) or randomly positioned crescents (76%) of Prospero/Numb (Figure 2; 10Kraut R. Chia W. Jan L.Y. Jan Y.N. Knoblich J.A. Nature. 1996; 383: 50-55Crossref PubMed Scopus (313) Google Scholar). Prospero and Numb are colocalized in the randomly-positioned crescents, but the crescents are not aligned with the mitotic spindle. Thus, Inscuteable does not control Prospero/Numb localization indirectly via spindle orientation. Nor does Inscuteable control Prospero/Numb localization by competition for an apical binding site, because there is a clear lateral gap between apical Inscuteable and basal Prospero/Numb crescents (10Kraut R. Chia W. Jan L.Y. Jan Y.N. Knoblich J.A. Nature. 1996; 383: 50-55Crossref PubMed Scopus (313) Google Scholar). However, ectopic Inscuteable does not alter the uniform localization of Numb in the ectoderm, even though it triggers a vertical spindle axis. Thus, Inscuteable has two independent functions: it is necessary and sufficent for triggering vertical spindle orientation, and it is necessary for basal Prospero/Numb localization. Previous work has shown that Prospero/Numb localization is largely independent of both microtubules and microfilaments (7Knoblich J.A. Jan L.Y. Jan Y.N. Nature. 1995; 377: 624-627Crossref PubMed Scopus (407) Google Scholar). In contrast, Inscuteable localization is independent of microtubules, but absolutely requires microfilaments (10Kraut R. Chia W. Jan L.Y. Jan Y.N. Knoblich J.A. Nature. 1996; 383: 50-55Crossref PubMed Scopus (313) Google Scholar). This difference between the cytoskeletal dependence of Prospero/Numb and Inscuteable is illustrated by the presence of a Prospero crescent and absence of an Inscuteable crescent in the same mitotic neuroblast in a Cytochalasin D–treated embryo (10Kraut R. Chia W. Jan L.Y. Jan Y.N. Knoblich J.A. Nature. 1996; 383: 50-55Crossref PubMed Scopus (313) Google Scholar). These results, taken together with the observation that Inscuteable protein contains predicted SH3 and ankyrin domains, which are implicated in cytoskeletal interactions, raises the possibility that Inscuteable binds microfilaments or F-actin–binding proteins. The latter is more likely, because neuroblasts have a uniform distribution of cortical F-actin at the time of Inscuteable localization (15Spana E.P. Kopczynski C. Goodman C.S. Doe C.Q. Development. 1995; 121: 3489-3494Crossref PubMed Google Scholar). The apical/basal polarity cues controlling Inscuteable localization must be present in the ectoderm, because apical localization of Inscuteable can be detected in ectodermal cells before they form neuroblasts. Furthermore, these cues may be common to all ectodermal epithelia: ectopically-expressed Inscuteable shows apical localization in lateral ectoderm that never produces neuroblasts (10Kraut R. Chia W. Jan L.Y. Jan Y.N. Knoblich J.A. Nature. 1996; 383: 50-55Crossref PubMed Scopus (313) Google Scholar). Dividing neuroblasts show transient apical localization of Inscuteable during prophase/metaphase of each cell cycle, despite having lost most epithelial characteristics (e.g., apical junctions and related proteins). Thus, the apical/basal polarity cues controlling Inscuteable localization are likely to be present in all ectodermal epithelia and maintained in dividing neuroblasts. With the rapidity of two hybrid screens, and the possibility of identifying genetic modifiers of the inscuteable phenotype, it is certain that we will soon have candidates for the apical/basal cues controlling Inscuteable localization. Understanding the mechanisms that couple asymmetric localization of cell fate determinants and spindle orientation has come from Drosophila (reviewed here) as well as yeast and C. elegans (reviewed by3Chang F. Drubin D.G. Curr. Biol. 1996; 6: 651-654Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 11Rhyu M.S. Knoblich J.A. Cell. 1995; 82: 523-525Abstract Full Text PDF PubMed Scopus (66) Google Scholar). In all three organisms, cell fate determinants controlling sibling cell fate have been identified (e.g., Ash1p in yeast, SKN-1 in C. elegans, and Prospero/Numb in flies), as well as mutations disrupting localization of these determinants (e.g. “she” mutants in yeast, “par” mutants in worms, and the inscuteable mutant in flies), yet, surprisingly, all genes sequenced to date are unrelated. Rapid progress can be expected following the cloning and characterization of homologous genes from each organism, as well as by using available genetic and biochemical methods to identify new genes controlling spindle orientation and asymmetric localization in each organism. Erratum et al.CellOctober 18, 1996In Brief Full-Text PDF Open Archive" @default.
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• W2060976363 title "Spindle Orientation and Asymmetric Localization in Drosophila: Both Inscuteable?" @default.
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