Interior nervous system

Surface epidermis

Neuroblasts and GMCs in different locations exhibit different patterns of gene expression, an indicator of their fates. Analysis of fly mutants led to the discovery of key proteins that participate in creating specific neuroblasts, inhibiting epidermal cells from becoming neuroblasts, and directing neuroblasts to divide asymmetrically.

Apical Baz/Par6/aPKC Complex A ternary complex of proteins, referred to as the apical complex, is located at the end of a fly neuroblast that will become the "new" neuroblast

▲ FIGURE 22-24 Localized proteins that control asymmetric cell division in the Drosophila neuroblast. (a) The apical complex (blue), which consists of three proteins (Baz, Par6, and aPKC), is localized in ectoderm cells and in delaminating neuroblasts. As a neuroblast begins dividing, Miranda protein (orange) accumulates at the apical side and then moves to the basal side, where it will be incorporated into the ganglion mother cell (GMC). The second basal component, the Numb protein (green), is detected only basally. Mutations in genes that encode polarized proteins disrupt asymmetric cell division. (b) Motor protein-mediated transport along cytoskeletal filaments is thought to localize the apical and basal complexes. Actin microfilaments (red) lie just under the cell surface at all times. Microtubules (blue) radiate from the centrosome during interphase and then assemble into the mitotic spindle, attached to the duplicated centrosomes, during cell division. Note that in the neuroblast-GMC division the centrosome is skewed to the neuroblast end of the cell, and the chromosomes (light gray) are diagrammed lined up on the spindle. [Adapted from C. Q. Doe and B. Bowerman, 2001, Curr. Opin. Cell Biol. 13:68.]

in the process of division. This complex is already localized at one end of all ectoderm cells. It stays at the apical end as a prospective neuroblast delaminates from the ectodermal sheet (Figure 22-24a, left). Three proteins compose the apical complex: Baz, Par6, and aPKC, the last being an isoform of protein kinase C. The Baz/Par6/aPKC complex persists at the apical end from late interphase (G2 stage) until late anaphase in mitosis and then disperses or is destroyed (see Figure 20-29 for mitotic stages). After each neuroblast division, the complex re-forms at the apical end of the progeny neuroblast in the next interphase. It remains unclear how polarity information is preserved through telophase, since no known proteins are localized during that time. As noted previously, the very first C. elegans cell division after fertilization is asymmetric, forming an AB cell and P1 cell, which have quite different fates (see Figure 22-9). Remarkably, a protein complex like the fly Baz/Par6/aPKC complex controls the asymmetry of the P1-AB division; similar protein complexes exist in mammals as well.

Two mechanisms control the apical localization of the Drosophila Baz/Par6/aPKC complex: the first operates in the ectoderm prior to neuroblast delamination; the second is active during the repeating divisions of delaminated neuro-blasts. The first mechanism involves at least three proteins, Scribble (Scrib), Discs-large (Dlg), and Lethal giant larvae (Lgl). These proteins are located in the cortical region of ectoderm cells (i.e., the region just below the plasma membrane), but are not polarized along the apical-basal axis of these cells. Thus, though necessary for the apical localization of the Baz/Par6/aPKC complex, the Scrib/Dlg/Lgl proteins probably are not sufficient. Once a neuroblast has separated from the ectoderm, the Ga subunit of the heterotrimeric G protein and two other proteins called Inscuteable and Partner of Inscuteable join the Baz/Par6/aPKC complex, forming a six-protein complex. These two additional proteins probably stabilize the Baz/Par6/aPKC complex. Reassembly of the entire complex at the apical end following each neuroblast division requires actin microfilaments (Figure 22-24b). Generally, asymmetric protein segregation requires actin but not tubulin, suggesting that motor protein-mediated transport of these proteins along microfilaments plays a role in their apical localization.

Basal Proteins In a dividing neuroblast two basal proteins are found at the end that will form a ganglion mother cell (GMC) at division (see Figure 22-24a, right). Localization of these proteins, including Miranda and Numb, at the basal end of neuroblasts requires the apical Baz/Par6/aPKC complex. The apical proteins set up polarity during interphase, and the polarity is read and interpreted by the machinery that transports Numb and Miranda at mitosis. The Numb protein is located throughout the cell during interphase; at prophase it becomes basally located. In contrast, Miranda initially assembles at the apical end; it then moves to the basal end at prophase. The apical Baz/Par6/aPKC complex forms even when either of the basal proteins is missing due to





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