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Regulation of Asymmetric Cell Division

During embryogenesis, the earliest stage in animal development, asymmetric cell division often creates the initial diversity that ultimately culminates in formation of specific differentiated cell types. Even in bacteria, cell division may yield unequal daughter cells, for example, one that remains attached to a stalk and one that develops flagella used for swimming. Essential to asymmetric cell division is polarization of the parental cell and then differential incorporation

▲ FIGURE 22-20 General features of asymmetric cell division. Various mechanisms can lead to asymmetric distribution of cytoplasmic components, such as particular proteins or mRNAs (red dots) to form a polarized parental cell. Division of a polarized cell will be asymmetric if the mitotic spindle is oriented so that the localized cytoplasmic components are distributed unequally to the two daughter cells, as shown here. However, if the spindle is positioned differently relative to the localized cytoplasmic components, division of a polarized cell may produce equivalent daughter cells.

transcription factors from these silent loci to the active MAT locus where they can be transcribed.

Interestingly, some haploid yeast cells can switch repeatedly between the a and a types. Mating-type switching occurs when the a allele occupying the MAT locus is replaced by the a allele, or vice versa. The first step in this process is catalyzed by HO endonuclease, which is expressed in mother cells but not in daughter cells. Thus mating-type switching occurs only in mother cells (Figure 22-21). Transcription of the HO gene is dependent on the Swi/Snf chromatin-remodeling complex (see Figure 11-37), the same complex that we encountered earlier in our discussion of myogenesis. Daughter yeast cells arising by budding from mother cells contain a protein called Ash1 that prevents recruitment of the Swi/Snf complex to the HO gene, thereby preventing its transcription. The absence of Ash1 from mother cells allows them to transcribe the HO gene.

Recent experiments have revealed how the asymmetry in the distribution of Ash1 between mother and daughter cells is established. ASH1 mRNA accumulates in the growing bud that will form a daughter cell due to the action of a myosin motor protein (Chapter 19). This motor protein, called Myo4p, moves the ASH1 mRNA, as a ribonucleoprotein complex, along actin filaments in one direction only, toward the bud (Figure 22-22). Two connector proteins tether ASH1 mRNA to the motor protein. By the time the bud separates from the mother cell, the mother cell is largely depleted of ASH1 mRNA and thus can switch mating type in the fol-

Division

/Vvisi

HO transcription No HO transcription

Switching No switching

of parts of the parental cell into the two daughters (Figure 22-20). A variety of molecular mechanisms are employed to create and propagate the initial asymmetry that polarizes the parental cell. In addition to being different, the daughter cells must often be placed in a specific orientation with respect to surrounding structures.

We begin with an especially well-understood example of asymmetric cell division, the budding of yeast cells, and move on to recently discovered protein complexes important for asymmetric cell divisions in multicellular organisms. We see in this example an elegant system that links asymmetric division to the process of controlling cell type.

Yeast Mating-Type Switching Depends upon Asymmetric Cell Division sS. cerevisiae cells use a remarkable mechanism to control the differentiation of the cells as the cell lineage progresses. Whether a haploid yeast cell exhibits the a or a mating type is determined by which genes are present at the MAT locus (see Figure 22-11). As described in Chapter 11, the MAT locus in the ,S. cerevisiae genome is flanked by two "silent," transcriptionally inactive loci containing the alternative a or a sequences (see Figure 11-28). A specific DNA rearrangement brings the genes that encode the a-specific or a-specific

▲ FIGURE 22-21 Specificity of mating-type switching in haploid yeast cells. Division by budding forms a larger mother cell (M) and smaller daughter cell (D), both of which have the same mating type as the original cell (a in this example). The mother can switch mating type during G1 of the next cell cycle and then divide again, producing two cells of the opposite a type. Switching depends on transcription of the HO gene, which occurs only in the absence of Ash1 protein. The smaller daughter cells, which produce Ash1 protein, cannot switch; after growing in size through interphase, they divide to form a mother cell and daughter cell. Orange cells and arrows indicate switch events.

► FIGURE 22-22 Model for restriction of mating-type switching to mother cells in S. cerevisiae. Ash1 protein prevents a cell from transcribing the HO gene whose encoded protein initiates the DNA rearrangement that results in mating-type switching from a to a or a to a. Switching occurs only in the mother cell, after it separates from a newly budded daughter cell, because Ash1 protein is present in the daughter cell but not in the mother cell. The molecular basis for this differential localization of Ash1 is the one-way transport of ASH1 mRNA into the bud. A linking protein, She2p, binds to specific 3' untranslated sequences in the ASH1 mRNA and also binds to She3p protein. This protein in turn binds to a myosin motor, Myo4p, which moves along actin filaments into the bud. [See S. Koon and B. J. Schnapp, 2001, Curr. Biology 11:R166-R168.]

lowing Gj before additional ASH1 mRNA is produced and before DNA replication in the S phase.

Budding yeasts use a relatively simple mechanism to create molecular differences between the two cells formed by division. In higher organisms, polarization of the parental cell involves many more participants, and in addition, as in yeast, the mitotic spindle must be oriented in such a way that each daughter cell receives its own set of cytoplasmic components. To illustrate these complexities, we focus on asymmetric division of neuroblasts in Drosophila. Genetic studies in C. elegans and Drosophila have revealed the key participants, a first step in understanding at the molecular level how asymmetric cell division is regulated in multicellular organisms.

ing to mediate lateral inhibition of their neighbors, causing them to retain the epidermal fate (see Figures 14-29 and 1536). The delaminating cells move inside and become spherical neuroblasts, while the prospective epidermal cells remain behind and close up to form a tight sheet.

Once formed, the neuroblasts undergo asymmetric divisions, at each division recreating themselves and producing a ganglion mother cell (GMC) at the basal side of the neuroblast (Figure 22-23). A single neuroblast will produce several GMCs; each GMC in turn forms two neurons. Depending on where they form in the embryo and consequent regulatory events, neuroblasts may form more or fewer GMCs.

Critical Asymmetry-Regulatory Proteins Are Localized at Opposite Ends of Dividing Neuroblasts in Drosophila

Fly neuroblasts, which are stem cells, arise from a sheet of ectoderm cells that is one cell thick. As in vertebrates, the Drosophila ectoderm forms both epidermis and the nervous system, and many ectoderm cells have the potential to assume either a neural or epidermal fate. Under the control of genes that become active only in certain cells, some of the cells increase in size and begin to loosen from the ectodermal layer. At this point, the delaminating cells use Notch signal-

► FIGURE 22-23 Asymmetric cell division during Drosophila neurogenesis. The ectodermal sheet (1) of the early embryo gives rise to both epidermal cells and neural cells. Neuroblasts, the stem cells for the nervous system, are formed when ectoderm cells enlarge, separate from the ectodermal epithelium, and move into the interior of the embryo ( 2- 4). Each neuroblast that arises divides asymmetrically to recreate itself and produce a ganglion mother cell (GMC) ( 5). Subsequent divisions of a neuroblast produce more GMCs, creating a stack of these precursor cells (6). Each GMC divides once to give rise to two neurons ( 7). Neuroblasts and their GMC descendants can have different fates depending on their location.

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Ectodermal cells

Neuroblast

Neuroblast

Interior nervous system

Surface epidermis

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