Gmc

Chromosome mutations. Mutations in any of the components of the apical complex, however, prevent the Miranda and Numb proteins from moving to the basal region. Instead they accumulate all around the cortical region or in clumps throughout the cell. The simplest idea, that the basal complexes form wherever the apical complex is absent, is probably wrong, since parts of the cell contain neither of these complexes.

Basally located molecules include Prospero protein, a transcription factor that contains a DNA-binding home-odomain; Miranda protein, which has a coiled-coil structure; Staufen, an RNA-binding protein; and prospero mRNA. During each round of neuroblast division, new Prospero protein is made during interphase and incorporated into the basal region, which is distributed to the GMC at the time of cleavage. In the absence of Prospero, GMCs do not transcribe the appropriate genes and do not develop into normal neurons. The localization of a transcription factor in the cytoplasm provides a link between the asymmetry of the cytoplasm and subsequent cell-fate determination, potentially explaining how a transcription factor is preferentially distributed to one of two daughter cells.

Orientation of the Mitotic Spindle Is Linked to Cytoplasmic Cell-Asymmetry Factors

For localized protein complexes to be differentially incorporated into two daughter cells requires that the plane of cell division be appropriately oriented. In dividing fly neuro-blasts, the mitotic spindle first aligns perpendicular to the apical-basal axis and then turns 90 degrees to align with it at the same time that the basal complexes become localized to the basal side (Figure 22-25). The apical complex, which is already in place before spindle rotation, controls the final orientation of the spindle. This is supported by the finding that mutations in any of the components of the apical complex eliminate the coordination of the spindle with apical-basal polarity, causing the spindle orientation to become random.

Spindle orientation is regulated by actin and myosin-related proteins. Mammalian Par6, a component of the apical complex, can bind two small GTPase proteins, Cdc42 and Rac1, that control the arrangement of actin microfilaments in the cytoskeleton (see Figure 19-29). The protein Lethal giant larvae (Lgl), a component of the Scrib/Dlg/Lgl asymmetry pathway, helps to localize Miranda basally in fly neuroblasts.

Lgl binds to myosin II, which functions in cytokinesis (see Figure 19-20). Lgl itself is uniformly localized around the cortex. Lgl is phosphorylated by the apical complex and may be inactivated on the apical side to allow basal Miranda accumulation. Two yeast proteins related to Lgl also bind to myosin II; they have been implicated in exocytosis and secretion, specifically in the docking of post-Golgi vesicles with the plasma membrane (Chapter 17). Mutations in the two yeast proteins suppress mutations in the myosin II gene. This observation is interpreted to mean that the function of myosin II in spindle orientation is opposite to that of the Lgl-like proteins: reduction of one protein's function is ameliorated by reduction of the other, restoring a semblance of the normal balance. In this case, therefore, myosin and Lgl probably act in opposite directions: myosin II moving Miranda or other materials to control spindle orientation and Lgl restraining it.

Further evidence for the importance of myosin in spindle orientation comes the finding that another myosin relative,

▲ EXPERIMENTAL FIGURE 22-25 Time-lapse fluorescence imaging reveals rotation of the mitotic spindle in asymmetrically dividing neuroblasts. Early Drosophila embryos were injected with a hybrid gene composed of the gene encoding green fluorescent protein (GFP) fused to the gene encoding Tau, a protein that binds to microtubules. At the top are time-lapse images of a single dividing neuroblast in a live embryo. The basal side is at the top, and the apical side at the bottom. At time 0, equivalent to prophase, the two centrosomes are visible on opposite sides of the cell. These function as the spindle poles; as mitosis proceeds the microtubules forming the mitotic spindle are assembled from the poles (see Figure 20-29). In successive images (at 32, 64, and 80 seconds), the bipolar spindle can be seem to form and rotate 90 degrees to align with the apical-basal axis, as schematically depicted at the bottom. [From J. A. Kaltschmidt et al., 2000, Nature Cell Biol. 2:7-12; courtesy of J. Kaltschmidt and A. H. Brand, Wellcome/CRC Institute, Cambridge University.]

myosin VI, binds directly to Miranda. In addition, mutations in myosin VI in flies prevent basal targeting of Miranda and simultaneously block proper spindle orientation. These various findings give us the beginning of a picture of how localized protein complexes are coordinated with cell division, so that each daughter cell receives the appropriate amounts of the various complexes.

At least some of the asymmetric cell division regulators discovered in flies and worms are present in vertebrates and have similar roles there. For example, mammalian Numb is required to maintain the neural stem-cell population. Evolutionary conservation of proteins and mechanisms facilitates rapid progress in research.

Cellular interactions regulate cell death in two fundamentally different ways. First, most cells, if not all, in multicellular organisms require signals to stay alive. In the absence of such survival signals, frequently referred to as trophic factors, cells activate a "suicide" program. Second, in some developmental contexts, including the immune system, specific signals induce a "murder" program that kills cells. Whether cells commit suicide for lack of survival signals or are murdered by killing signals from other cells, recent studies suggest that death is mediated by a common molecular pathway. In this section, we first distinguish programmed cell death from death due to tissue injury, then consider the role of trophic factors in neuronal development, and finally describe the evolutionarily conserved effector pathway that leads to cell suicide or murder.

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