Asymmetric Cell Division: A Persistent Issue?
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Citation
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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Wed May 25 15:50:33 EDT 2016
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http://hdl.handle.net/1721.1/91964
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Developmental Cell
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Asymmetric Cell Division: A Persistent Issue?
Christopher D. Aakre1 and Michael T. Laub1,2,*
1Department
of Biology
Hughes Medical Institute
Massachusetts Institute of Technology, Cambridge, MA 02139, USA
*Correspondence: laub@mit.edu
DOI 10.1016/j.devcel.2012.01.016
2Howard
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 lifetime (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 chemotherapeutics. Typical treatment regimens for
tuberculosis can last up to 9 months
and require the use of multiple drugs.
Why M. tuberculosis requires such extensive treatment is unclear, although it is
possible that heterogeneity in antibiotic
susceptibility—even within a clonal population 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 suggests that heterogeneity in mycobacteria
may also result from a deterministic process, 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 mycobacteria underscore the fundamental asymmetry 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 (Figure 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 specialization of daughter cells. For example,
in the oligotrophic bacterium Caulobacter
crescentus, different organelles are produced 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 mycobacteria also leverage this asymmetry
between the old and new pole to generate
diversity among daughter cells. With timelapse imaging of M. smegmatis, a nonpathogenic relative of M. tuberculosis,
the authors observe that individual cells
are highly variable in elongation rate and
in the symmetry of cell sizes after division compared to E. coli. To determine
whether this variability arises from differences 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 mechanistic basis for this growth asymmetry
is unclear, but could involve the protein
DivIVA/Wag31. In Streptomyces coelicolor, DivIVA marks sites for apical growth
and is sufficient to direct growth at ectopic 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 accelerator 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 accelerator 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, accelerators 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 possibility is that the slower growth rate of
Developmental Cell 22, February 14, 2012 ª2012 Elsevier Inc. 235
Developmental Cell
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A
B
C
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 understanding 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.
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 asymmetry 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.
alternator cells renders them more resistant 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 sensitive to the transcriptional inhibitor rifam-
picin, suggesting that there may be additional physiological differences between
alternators and accelerators that are not
yet clear.
The generation of heterogeneity that
results from unipolar growth may constitute 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-
Curtis, P.D., and Brun, Y.V. (2010). Microbiol. Mol.
Biol. Rev. 74, 13–41.
de Pedro, M.A., Quintela, J.C., Höltje, J.V., and
Schwarz, H. (1997). J. Bacteriol. 179, 2823–2834.
Hempel, A.M., Wang, S.B., Letek, M., Gil, J.A., and
Flärdh, 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., Abramovitch, 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
Philippe V. Afonso1 and Carole A. Parent1,*
1Laboratory 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
DOI 10.1016/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 migration 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-
236 Developmental Cell 22, February 14, 2012 ª2012 Elsevier Inc.
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