Cell division depends on sophisticated molecular machinery. However, wall-less forms of bacteria use a much simpler mechanism that mimics spontaneous division of synthetic lipid vesicles. Mercier et al. (2013) show that this “mechanical” division can be activated by increased lipid synthesis. Conceivably, the first cells divided via this route

Koonin, Eugene V.

Mulkidjanian, Armen Y.

Elsevier - Publisher Connector 

mouse model, despite normal in vitro
binding of mutant MeCP2 to ATRX? Third,
what is the structural basis for MeCP2
binding to 5hmC and 5mC? It is intriguing
that other MBD family members showed
no or much weaker binding to 5hmC,
although R133 is highly conserved
among the MBD family. The in vitro
binding properties of MeCP2 to 5hmC
also beg further confirmation of interac-
tion in vivo. Fourth, do posttranslational
modifications of MeCP2, which are
known to affect MeCP2 function (Guy
et al., 2011), regulate binding of MeCP2
to 5hmC and/or AT-rich DNA? Both
studies, while investigating neurons only
in the basal state, raise the possibility of
dynamic interactions between MeCP2
and different binding partners to regulate
chromatin structure, which can be
corroborated with dynamic changes of
5mC and 5hmC in neurons in response
to neuronal activity (Guo et al., 2011a,
and 2011b). Rapidly accumulating
evidence supports the contribution of942 Cell 152, February 28, 2013 ª2013 Elsevdiverse chromatin remodeling factors to
ASD. Baker et al. and Melle´n et al. high-
light the importance of incorporating
complex and dynamic chromatin struc-
tures into our understanding of RTT
and other ASDs. By identifying molecular
events triggered by MeCP2 dysfunction,
we will be able not only to identify
therapeutic targets for RTT and ASD
patients, but also to elucidate funda-
mental epigenetic regulatorymechanisms
in the brain.
ACKNOWLEDGMENTS
We thank the support by a Samsung Scholarship
to J.S., from NIH (HD069184, NS048271), MSCRF
and Dr. Miriam and Sheldon G. Adelson Medical
Research Foundation to G-l.M. and from NIH
(NS047344, ES021957) and SAFRI to H.S.REFERENCES
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Proc. Natl. Acad. Sci. USA 104, 2709–2714.Evolution of Cell Division: From Shear
Mechanics to Complex Molecular Machineries
Eugene V. Koonin1,* and Armen Y. Mulkidjanian2,3,4
1National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA
2School of Physics, University of Osnabru¨ck, 49069 Osnabru¨ck, Germany
3School of Bioengineering and Bioinformatics
4A.N. Belozersky Institute of Physico-Chemical Biology
Lomonosov Moscow State University, Moscow 119992, Russia
*Correspondence: koonin@ncbi.nlm.nih.gov
http://dx.doi.org/10.1016/j.cell.2013.02.008
Cell division depends on sophisticated molecular machinery. However, wall-less forms of bacteria
use a much simpler mechanism that mimics spontaneous division of synthetic lipid vesicles.
Mercier et al. (2013) show that this ‘‘mechanical’’ division can be activated by increased lipid
synthesis. Conceivably, the first cells divided via this route.Cell division, even in the relatively simple
bacterial and archaeal cells, is mediated
by highly complex, elaborate molecular
machinery. However, the cell-wall-defi-
cient L forms to which many bacteria
convert when cell wall biogenesis is in-hibited, in particular by cell-wall-targeting
antibiotics, bypass these mechanisms
and instead divide via a much simpler
mechanism that involves shape perturba-
tions, including blebbing, tubulation, and
vesiculation (Errington, 2013). In this issueof Cell, Mercier et al. (2013) show that the
switch to this ‘‘biophysical’’ mode of divi-
sion can be triggered by an increased lipid
synthesis that results in an increased cell
surface to volume ratio. The first cells,
up to the stage of the last universal cellular
Figure 1. Evolutionary Transition from Primitive ‘‘Mechanical’’ Cell Division to Complex Cell
Division Machineries
Under the depicted scenario, the first protocells possessed abiogenic membranes and divided via the
mechanical mode. The division of these primitive cells could have been driven by environmental fluctu-
ations such as periodic evaporation in shallow water basins. The mechanical division persisted through
the stage of the last universal cellular ancestor (LUCA) that conceivably synthesized primitive and
chemically simple membranes. Complex, modern-type membranes and cell division machineries evolved
independently in the bacterial and archaeal lines of descent, possibly driven by the evolution of cell
envelopes.
Primitive and chemically simple membranes are shown with dashed lines, and advanced modern type
membranes are shown with solid lines. The red lines within the ‘‘cells’’ show the genome: primitive pro-
tocells are shown with multiple segments (possibly RNA molecules), whereas the LUCA and the ancestral
archaeon and bacterium are shown with a typical single circular chromosome.ancestor (LUCA), could have divided via
this type of generic mechanical process.
In the majority of the bacteria and
archaea, the key structure involved in divi-
sion is the Z ring that consists of the FtsZ
GTPase, the prokaryotic homolog of
tubulins (Adams and Errington, 2009).
The Z ring assembles in the mid plane of
a dividing bacterial or archaeal cell. The
constriction of the Z ring, facilitated by
cytoskeleton typically comprised of the
actin homologMreB and a variety of regu-
latory protein and accompanied by pepti-
doglycan septum formation, leads to
segregation of the daughter cells (Adams
and Errington, 2009). Although the FtsZ-
centered system operates in the majority
of bacteria and archaea, it is by no means
the universal cell division mechanism in
prokaryotes. The Crenarchaeota, one
of the major archaeal phyla, lack FtsZand instead possess one of the two
distinct alternative actin-based and
ESCRT-III-based cell division systems
(Makarova et al., 2010). The FtsZ protein
is also missing in some Euryarchaeota
(Makarova et al., 2010) and bacteria,
especially those of the Verrucomicrobia-
Planctomycetes-Chlamydia superphylum
(Bernander and Ettema, 2010). Moreover,
many archaea encodemore than one divi-
sion system, suggestive of a complex
scenario for the evolution of cell division
in prokaryotes (Makarova et al., 2010).
Strikingly, the wall-less L forms
bypass the entire FtsZ-centered division
machinery and instead divide via the
simple ‘‘mechanical’’ route (Errington,
2013). Mercier et al. (2013) identify
a trigger of the division of Bacillus subtilis
L forms. The key observation is that
regulatory mutations that result in anCell 152,increased fatty acid production and the
consequent excess membrane formation
induce the division of the L forms. Accord-
ing to the model proposed by Mercier
et al., the resulting increase in the surface
to volume ratio leads to cell deformation
accompanied by torsional stress that is
released by scission into daughter cells
(Mercier et al., 2013).
Mercier et al. propose that the remark-
ably simple ‘‘biophysical’’ mode of cell
division is a backup process that is in-
ducedwhen cell wall synthesis is compro-
mised. There is a striking parallel between
this mechanism of L-form division and the
previous observations that simple fatty
acid vesicles, studied as possible models
of primordial protocells, undergo shear-
induced division when their surface to
volume ratio is artificially increased by
addition of fatty acids (Zhu and Szostak,
2009). Recently, Budin et al. have shown
that addition of fatty acids, hardly plau-
sible under primordial conditions, could
be replaced by evaporating the sample,
which increased the efficient concentra-
tion of amphiphlic molecules in the solu-
tion (Budin et al., 2012).
Mercier et al. argue that the biophysical
cell division process is not only simple,
but actually primitive, so that the division
of L forms might mimic the mode of cell
division at the early stages of the evolution
of life. A tentative scenario of the evolution
of cell division following this hypothesis is
depicted in Figure 1.
The first cell-like organisms (Figure 1)
that could have existed already in the
RNA world would have been fully depen-
dent on abiotically produced amphiphilic
molecules, such as fatty acids and
phosphorylated branched hydrocarbons
(Budin et al., 2012; Dibrova et al., 2012).
In shallow water basins, the evaporation,
driven by solar or geothermal heat and
wind, would lead to concentration of
solutes and hence to the growth of mem-
brane vesicles ultimately leading to their
division (Budin et al., 2012). Thus, the cell
division cycles could follow daily environ-
mental changes; such fluctuations (Budin
et al., 2012) would have been particularly
pronounced at arid, vapor-dominated
geothermal fields that havebeen identified
as plausible hatcheries for the emergence
of cells (Mulkidjanian et al., 2012).
The transition to the complex mecha-
nisms of cell division might have beenFebruary 28, 2013 ª2013 Elsevier Inc. 943
driven by the evolution of cell walls, which
although energetically costly, made cells
independent of the osmolarity of their
habitats (Mercier et al., 2013). The struc-
tures and chemical compositions of the
cell walls in bacteria and archaea are
drastically different (typically, peptido-
glycan cell envelopes and paracrystalline
proteinaceous S layers, respectively)
(Albers and Meyer, 2011). Thus, this
evolutionary scenario seems to imply
that the early cells, from the first hypothet-
ical cell-like entities to the LUCA, all
divided via the primitive mechanical
route. Given that the chemical structures
of bacterial and archaeal membrane
lipids are different as well (Albers and
Meyer, 2011), it seems likely that the
LUCA also possessed chemically simple
membranes (Dibrova et al., 2012) that
were conducive to the mechanical divi-
sion. The scenario further implies that
evolution of cell walls could trigger the
independent emergence of distinct cell944 Cell 152, February 28, 2013 ª2013 Elsevdivision machineries at the early stages
of the evolution of bacteria and archaea
(Figure 1). Accordingly, the FtsZ-centered
cell division system is likely to be ances-
tral in bacteria, whereas the common
ancestor of the extant archaea would
employ one (or both) of the alternative,
actin-based or ESCRT-III-based cell
division systems (Makarova et al., 2010)
(Figure 1). Under this scenario, the FtsZ-
centered system, despite its current
broad representation in archaea (Makar-
ova et al., 2010), was acquired from
bacteria via horizontal gene transfer.
Regardless of the details of evolution
of the cell division machineries, the
findings of Mercier et al. (2013) provide
at least one piece of the solution to
the classical Darwinian challenge of
the origin of this seemingly ‘‘irreducibly’’
complex system. Furthermore, these
results should stimulate further experi-
mentation aimed at modeling of primitive
protocells.ier Inc.REFERENCES
Adams, D.W., and Errington, J. (2009). Nat. Rev.
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Bernander, R., and Ettema, T.J. (2010). Curr. Opin.
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Budin, I., Debnath, A., and Szostak, J.W. (2012).
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Dibrova, D.V., Chudetsky, M.Y., Galperin, M.Y.,
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Errington, J. (2013). Open Biol. 3, 120143.
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Evolution of Cell Division: From Shear Mechanics to Complex Molecular Machineries 

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Evolution of Cell Division: From Shear Mechanics to Complex Molecular Machineries

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