Asymmetric Cell Division: A Persistent Issue?

Asymmetric Cell Division: A Persistent Issue?

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Aakre, Christopher D., and Michael T. Laub. “Asymmetric Cell

Division: A Persistent Issue?” Developmental Cell 22, no. 2

(February 2012): 235–236. © 2012 Elsevier Inc.

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http://dx.doi.org/10.1016/j.devcel.2012.01.016

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Elsevier

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Final published version

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http://hdl.handle.net/1721.1/91964

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Article is made available in accordance with the publisher's

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Asymmetric Cell Division: A Persistent Issue?

1_{Department of Biology}

2_{Howard Hughes Medical Institute}

Massachusetts Institute of Technology, Cambridge, MA 02139, USA *Correspondence:laub@mit.edu

DOI10.1016/j.devcel.2012.01.016

Heterogeneity within a clonal population of cells can increase survival in the face of environmental stress. In

a recent issue of

Science,

Aldridge et al. (2012)

demonstrate that cell division in mycobacteria is asymmetric,

producing daughter cells that differ in size, growth rate, and susceptibility to antibiotics.

More than two billion people worldwide are infected with tuberculosis, and ten percent of these individuals are expected to develop active disease during their life-time (Russell et al., 2010). The remarkable success of Mycobacterium tuberculosis in the modern age of antibiotics can be attributed, in part, to its ability to survive prolonged treatment with chemothera-peutics. Typical treatment regimens for tuberculosis can last up to 9 months and require the use of multiple drugs. Why M. tuberculosis requires such exten-sive treatment is unclear, although it is possible that heterogeneity in antibiotic susceptibility—even within a clonal popu-lation of cells—may play a major role.

Heterogeneity can arise stochastically, as is probably the case in the formation of dormant cells called persisters that are highly tolerant to antibiotics (Lewis, 2010). Intriguingly, a recent study sug-gests that heterogeneity in mycobacteria may also result from a deterministic pro-cess, namely asymmetric cell division (Aldridge et al., 2012). With time-lapse microscopy, Aldridge et al. (2012) find that every cell division for mycobacteria produces daughter cells that grow at different rates. This asymmetry ultimately stems from the fact that mycobacterial cells preferentially grow from only one pole. Cell division thus produces one fast-growing daughter cell containing the growth pole, and another, slower-growing daughter cell that must assemble a growth pole de novo. Importantly, the authors find that these growth rate differences are associated with different antibiotic susceptibilities.

These recent findings with mycobac-teria underscore the fundamental asym-metry of cell division in all rod-shaped bacteria. Their cell divisions typically occur

through binary fission, producing cells with a ‘‘new’’ pole proximal to the division plane and an ‘‘old’’ pole distal to it ( Fig-ure 1A). Thus, even division events that produce apparently identical daughter cells—as in E. coli—have an underlying asymmetry. Indeed, E. coli cells with older poles tend to grow more slowly and have an increased risk of dying compared to cells with younger poles (Stewart et al., 2005). In other cases, cells exploit this asymmetry to generate functional spe-cialization of daughter cells. For example, in the oligotrophic bacterium Caulobacter

crescentus, different organelles are

pro-duced at the poles, with a tubular stalk located at the old pole and a flagellum synthesized at the new pole during each cell cycle (Curtis and Brun, 2010); every cell division for C. crescentus thus yields dimorphic daughter cells (Figure 1B).

Aldridge et al. (2012) find that myco-bacteria also leverage this asymmetry between the old and new pole to generate diversity among daughter cells. With time-lapse imaging of M. smegmatis, a non-pathogenic relative of M. tuberculosis, the authors observe that individual cells are highly variable in elongation rate and in the symmetry of cell sizes after divi-sion compared to E. coli. To determine whether this variability arises from differ-ences in the growth rate of daughter cells, the authors pulse-label the cell wall with a fluorescent amine-reactive dye and then track the growth of the unlabeled poles. Surprisingly, they find that new growth occurs almost exclusively from the old pole. This contrasts with rod-shaped bacteria like E. coli that grow mainly through the insertion of new cell wall material throughout the cell body (de Pedro et al., 1997). The localization of growth at the old pole in mycobacteria

creates two classes of cells after division: ‘‘accelerators’’ that inherit the old pole and continue growing and ‘‘alternators’’ that must fashion a new growth pole before elongating (Figure 1C). The mech-anistic basis for this growth asymmetry is unclear, but could involve the protein DivIVA/Wag31. In Streptomyces

coeli-color, DivIVA marks sites for apical growth

and is sufficient to direct growth at ec-topic sites when overproduced (Hempel et al., 2008). The mycobacterial homolog Wag31 was previously found to strongly localize to the old pole and to exhibit a delay before localization to the new pole (Kang et al., 2008).

Further single-cell measurements from

Aldridge et al. (2012)reveal that acceler-ator cells tend to elongate faster than alternator cells, as expected if alternators must generate a new growth pole after each division. Accelerators are also born at a larger size, suggesting that unipolar growth continues even after formation of the division septum. Interestingly, the authors observe that the age of the accel-erator cell, and hence the age of the growth pole, also has an effect on growth rate and size after division. Accelerators that have gone through two division events elongate faster and are born at a larger size than accelerators who have gone through only one division event. This trend holds up only to a certain point—in some microcolonies, accelera-tors appear to ‘‘reset’’ their growth rate and grow more slowly than their sister cells with younger growth poles.

The net result of this unusual unipolar growth is a population of cells that is clearly heterogeneous in cell size and growth rate. But is there a functional purpose to such heterogeneity? One pos-sibility is that the slower growth rate of

alternator cells renders them more re-sistant to antibiotics, particularly those targeting processes that occur only in growing cells, such as cell wall synthesis. Consistent with this notion, the authors demonstrate that alternator cells are more resistant to the cell wall synthesis inhibitors meropenem and cycloserine. However, alternator cells are more sensi-tive to the transcriptional inhibitor

rifam-picin, suggesting that there may be addi-tional physiological differences between alternators and accelerators that are not yet clear.

The generation of heterogeneity that results from unipolar growth may con-stitute a type of bet-hedging strategy against antibiotics or other environmental stresses (Veening et al., 2008). More work is clearly needed to elucidate how

unipo-lar growth occurs, how it is regulated both temporally and spatially, and what all of its functional consequences are. The work of Aldridge et al. (2012) with mycobacteria indicates that such studies could have major consequences for un-derstanding tuberculosis and bacterial pathogenesis.

REFERENCES

Aldridge, B.B., Fernandez-Suarez, M., Heller, D., Ambravaneswaran, V., Irimia, D., Toner, M., and Fortune, S.M. (2012). Science 335, 100–104. Curtis, P.D., and Brun, Y.V. (2010). Microbiol. Mol. Biol. Rev. 74, 13–41.

de Pedro, M.A., Quintela, J.C., Ho¨ltje, J.V., and Schwarz, H. (1997). J. Bacteriol. 179, 2823–2834. Hempel, A.M., Wang, S.B., Letek, M., Gil, J.A., and Fla¨rdh, K. (2008). J. Bacteriol. 190, 7579–7583. Kang, C.M., Nyayapathy, S., Lee, J.Y., Suh, J.W., and Husson, R.N. (2008). Microbiology 154, 725–735.

Lewis, K. (2010). Annu. Rev. Microbiol. 64, 357–372.

Russell, D.G., VanderVen, B.C., Lee, W., Abramo-vitch, R.B., Kim, M.-J., Homolka, S., Niemann, S., and Rohde, K.H. (2010). Cell Host Microbe 8, 68–76.

Stewart, E.J., Madden, R., Paul, G., and Taddei, F. (2005). PLoS Biol. 3, e45.

Veening, J.-W., Smits, W.K., and Kuipers, O.P. (2008). Annu. Rev. Microbiol. 62, 193–210.

Neutrophils under Tension

1_{Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda,}

MD 20892, USA

*Correspondence:parentc@mail.nih.gov

DOI10.1016/j.devcel.2012.01.017

An article by

Houk et al. (2012)

in

Cell provides insight into the mechanisms confining membrane protrusions

to the front of migrating neutrophils. The authors rule out a role for diffusion of inhibitory signals and show that

membrane tension is necessary and sufficient to restrict signals that lead to protrusions.

Neutrophils readily polarize in response to chemoattractants and migrate through coordinated protrusions at their leading edge and retractions at their back. Efficient and persistent neutrophil migra-tion requires the maintenance of cell

polarization. When cells migrate up a chemoattractant gradient, polarization maintenance can be envisioned as the continuous response to an anisotropic environment. However, when neutrophils migrate in an isoform, isotropic

environ-ment, maintained polarization suggests that a semiautonomous excitable network is activated (Iglesias and Devreotes, 2011).

Positive and negative feedback loops have been implicated in maintaining

A B C

Figure 1. Asymmetric Cell Division in Bacteria

(A) All cell divisions in rod-shaped bacteria are asymmetric, in that one daughter cell inherits the ‘‘new’’ pole (green) from a previous division and the other inherits the ‘‘old’’ pole (red). In some bacteria, this asym-metry is used to create functional specialization of daughter cells.

(B) In C. crescentus, different polar appendages form at the new and old poles, leading to dimorphic daughter cells.

(C) In Mycobacterium, cells preferentially grow at the old pole (marked with an arrow). Daughter cells that inherit the old pole, called accelerators, continue growing whereas those inheriting the new pole, called alternators, must form a new growth pole before elongating.

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