Myxobacteria: Moving, Killing, Feeding, and Surviving Together

micb-07-00781 May 25, 2016 Time: 15:38 # 1
REVIEW
published: 26 May 2016
doi: 10.3389/ micb.2016.00781
Edi ed by:
José Edua do González-Pas o ,
Cen o de As obiología – Consejo
Supe io de In es igaciones
Cien í icas–Ins i u o Nacional
de Técnica Ae oespacial, Spain
Re iewed by:
Da id Edwa d Whi wo h,
Abe ys wy h Uni e si y, UK
Law ence Joseph Shimke s,
Uni e si y o Geo gia, USA
*Co espondence:
José Muñoz-Do ado
jdo ado@ug .es
Special y sec ion:
This a icle was submi ed o
Mic obial Physiology and Me abolism,
a sec ion o he jou nal
F on ie s in Mic obiology
Recei ed: 01 Ap il 2016
Accep ed: 09 May 2016
Published: 26 May 2016
Ci a ion:
Muñoz-Do ado J, Ma cos-To es FJ,
Ga cía-B a o E, Mo aleda-Muñoz A
and Pé ez J (2016) Myxobac e ia:
Mo ing, Killing, Feeding,
and Su i ing Toge he .
F on . Mic obiol. 7:781.
doi: 10.3389/ micb.2016.00781
Myxobac e ia: Mo ing, Killing,
Feeding, and Su i ing Toge he
José Muñoz-Do ado*, F ancisco J. Ma cos-To es, Elena Ga cía-B a o,
Au elio Mo aleda-Muñoz and Juana Pé ez
Depa amen o de Mic obiología, Facul ad de Ciencias, Uni e sidad de G anada, G anada, Spain
Myxococcus xan hus, like o he myxobac e ia, is a social bac e ium ha mo es and
eeds coope a i ely in p eda o y g oups. On su aces, od-shaped ege a i e cells mo e
in sea ch o he p ey in a coo dina ed manne , o ming dynamic mul icellula g oups
e e ed o as swa ms. Wi hin he swa ms, cells in e ac wi h one ano he and use
wo sepa a e locomo ion sys ems. Ad en u ous mo ili y, which d i es he mo emen
o indi idual cells, is associa ed wi h he sec e ion o slime ha o ms ails a he
leading edge o he swa ms. I has been p oposed ha cellula a ic along hese ails
con ibu es o M. xan hus social beha io ia s igme gic egula ion. Howe e , mos o
he cells a el in g oups by using social mo ili y, which is cell con ac -dependen and
equi es a la ge numbe o indi iduals. Exopolysaccha ides and he e ac ion o ype IV
pili a al e na e poles o he cells a e he engines associa ed wi h social mo ili y. When
he swa ms encoun e p ey, he popula ion o M. xan hus lyses and akes up nu ien s
om nea by cells. This coope a i e and highly densi y-dependen eeding beha io has
he ad an age ha he pool o hyd oly ic enzymes and o he seconda y me aboli es
sec e ed by he en i e g oup is sha ed by he communi y o op imize he use o he
deg ada ion p oduc s. This mul icellula beha io is especially obse ed in he absence
o nu ien s. In his condi ion, M. xan hus swa ms ha e he abili y o o ganize he gliding
mo emen s o 1000s o ods, synch onizing ippling wa es o oscilla ing cells, o o m
mac oscopic ui ing bodies, wi h h ee subpopula ions o cells showing di ision o labo .
A small ac ion o cells ei he de elop in o esis an myxospo es o emain as pe iphe al
ods, while he majo i y o cells die, p obably o p o ide nu ien s o allow agg ega ion
and spo e di e en ia ion. Spo ula ion wi hin mul icellula ui ing bodies has he bene i
o enabling su i al in hos ile en i onmen s, and inc eases ge mina ion and g ow h a es
when cells encoun e a o able condi ions. He ein, we e iew how hese social bac e ia
coope a e and e iew he main cell–cell signaling sys ems used o communica ion o
main ain mul icellula i y.
Keywo ds: Myxococcus xan hus, mo ili y, p eda ion, p oka yo ic de elopmen , mul icellula i y
INTRODUCTION
The exis ence o mul icellula o ganisms in all he lineages o he ee o li e sugges s ha
mul icellula i y eme ged on mul iple occasions in he cou se o e olu ion (Rokas, 2008;A a ind
e al., 2009). In he p oka yo ic domains (Bac e ia and A chaea), mul iple eme gences o
mul icellula i y ha e also been obse ed (G osbe g and S a hmann, 2007). These p oka yo es,
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Muñoz-Do ado e al. Myxobac e ia Mul icellula i y
hough simple in hei a chi ec u e and mo phology, and wi h
only a small numbe o di e en ia ed cells ypes, g ea ly esemble
highe mul icellula o ganisms. Al hough he cells in clonal
popula ions o mul icellula p oka yo es sha e he same gene ic
ma e ial, cells can di e signi ican ly om one ano he in hei
p ope ies and beha io s. The pheno ypic a ia ions be ween
iden ical indi iduals a e mainly due o he egula ion o gene
exp ession in esponse o di e en mic oen i onmen s, bu
hey can also be a consequence o andom cellula a iabili y
due o una oidable s ochas ic luc ua ions in gene ic ci cui s
ha egula e cellula unc ions (Elda and Elowi z, 2010; an
Vlie and Acke mann, 2015). The mos impo an bene i
o such pheno ypic a ia ions is he di ision o labo , wi h
di e en cell ypes specialized in di e en unc ions wo king
oge he . Such di ision o labo , combined wi h cell–cell
adhesion and coo dina ed in e cellula communica ion, pe mi s
he whole popula ion o unc ion mo e e icien ly, o achie e
new synch onized unc ionali ies, and o de elop complex g oup
beha io s, such as a oidance o p eda ion and o non-coope a i e
indi iduals and imp o emen in e iciency o nu ien acquisi ion
(Acke mann e al., 2008;Aguila e al., 2015).
The e a e nume ous unicellula mic oo ganisms ha display
incipien mul icellula i y, such as he o ma ion o ilamen s o
simple clus e s. These ypes o mani es a ions may be he esul o
simple agg ega ion ha equi es an ex acellula ma ix (ECM),
incomple e cell ission a e di ision, o o ma ion o cells joined
a hei ends ha sha e he pe iplasm o e en he cy oplasm
(Claessen e al., 2014;Lyons and Kol e , 2015). Examples a e
ound in unicellula ungi such as Saccha omyces ce e isiae,
a chaea such as Me hanosa cina, and many bac e ia o he
phyla Cyanobac e ia,Ac inobac e ia,Chlo o lexi,P o eobac e ia,
and Fi micu es (Maca io and Conway de Maca io, 2001;
Claessen e al., 2014;Lyons and Kol e , 2015). Ano he class
o mul icellula i y is he o ma ion o mo e s able agg ega es,
which includes he o ma ion o bio ilms and swa ms. This
class is widesp ead among bac e ia such as Bacillus and P o eus
(Lyons and Kol e , 2015). Likewise, he e is a smalle numbe
o species ha display e en mo e complex mul icellula i y
(such as Caulobac e ,Pseudomonas, and myxobac e ia),
which consis s o he cons uc ion o pa e ned mul icellula
s uc u es. This complex beha io equi es sel - ecogni ion,
spa ial mo phogenesis, cell di e en ia ion, di ision o labo ,
in e cellula communica ion, and coope a ion among indi idual
cells (Kea ns, 2007;Lopez and Kol e , 2010;Koschwanez e al.,
2011;Claessen e al., 2014;Lyons and Kol e , 2015). These
bac e ia a e well-o ganized coope a o s ha unc ion mo e
e icien ly as mul icellula uni s.
Myxobac e ia a e one o he bac e ial g oups ha ha e
e ec i ely made he ansi ion om single cell o mul icellula
li e, exhibi ing mul i ace ed coope a i e beha io s and
mul icellula de elopmen compa able in sophis ica ion
o ha seen in mac oscopic social o ganisms. In deple ed
condi ions, hey o m mul icellula bio ilms called ui ing
bodies ha a y om simple mounds o con olu ed h ee
dimensional s uc u es, wi hin which some bac e ia al uis ically
de elop in o non- ep oduc i e cells, while o he s di e en ia e
in o esis an and ep oduc i e spo es (Shimke s, 1999).
Fu he mo e, hei mul icellula beha io encompasses o he
aspec s o hei li e cycle such as mass p eda ion and coope a i e
mo ili y. Myxobac e ia, pa icula ly du ing he ui ing body
o ma ion p ocess, ep esen an in e es ing case on he
pa h o obliga e mul icellula i y. Coope a ion is no s ic ly
necessa y in a a o able en i onmen , no hey do en e
in o a mul icellula s a e wi hou he app op ia e condi ions,
such as high cell densi y, a solid su ace, and s a a ion.
The e o e, mul icellula i y in myxobac e ia is ansi o y, and
no obliga o y, as opposed o obliga e mul icellula i y, whe e
o ganisms ha e no choice bu o be mul icellula (An ónio
and Schulze-Makuch, 2012). Indeed, Velice e al. (1998)
demons a ed by using labo a o y expe imen al e olu ion ha
mul icellula i y in myxobac e ia can be los i i is no needed.
Unde condi ions in which mul icellula i y is no ad an ageous
(e.g., liquid, shaken cul u es), de ec s in ui ing body o ma ion,
spo ula ion and mo ili y only eme ged a e 1000 gene a ions,
sugges ing ha hese social beha io s we e all insigni ican o
i ness.
Myxococcus xan hus, A MODEL FOR
MULTIFACETED COOPERATIVE
BEHAVIORS IN BACTERIA
The bes cha ac e ized myxobac e ium is Myxococcus xan hus.
I s li e cycle comp ises wo phases ha highligh he social
na u e o his o ganism: coope a i e p eda ion and mul icellula
de elopmen (Figu e 1). Bo h mul icellula p ocesses a e
media ed by he coo dina ed mo emen o cells using wo
mo ili y sys ems (Figu e 2), indi idual mo ili y (ad en u ous
mo ili y o A-mo ili y) and g oup mo ili y (social mo ili y
o S-mo ili y), which a e deal wi h in he nex sec ion.
In he p esence o nu ien s, cells mo e in a coo dina ed
manne , o ming mul icellula bio ilms known as swa ms.
When swa ms make con ac wi h p ey, housands o cells
e en ually pene a e he p ey colony and lyse he cells
(Figu e 1A) (Be leman and Ki by, 2009;Pé ez e al., 2016).
This g oup p eda ion s a egy a o s he swa m hyd olyzing
ex acellula biopolyme s using common exoenzymes and,
hus, making he mos e icien possible use o he a ailable
sou ces o nu i ion. Howe e , upon s a a ion, cells mo ing
collec i ely s a a de elopmen al p ocess and exchange
ex acellula chemical signals as well as physical con ac signals
o o m millime e -long up igh ui ing bodies (Kaise , 2004;
Mau iello e al., 2010). These ma u e mul icellula s uc u es
(Figu e 1B), illed wi h en i onmen ally esis an myxospo es
(O’Conno and Zusman, 1991a), a e su ounded by wo
di e en subpopula ions showing di ision o labo (Figu e 1B):
a monolaye o aligned pe iphe al ods which a e dis inc om
ege a i e cells and spo es (O’Conno and Zusman, 1991b),
and cells ha unde go al uis ic obliga o y au olysis h ough a
de elopmen ally p og ammed cell dea h (PCD; Wi eman and
Dwo kin, 1977;Na iya and Inouye, 2008). Wi hin he ui ing
bodies he myxospo es a e i mly bound oge he , hence upon
ge mina ion he whole popula ion s ays oge he o c ea e a new
communi y.
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Muñoz-Do ado e al. Myxobac e ia Mul icellula i y
FIGURE 1 | Myxococcus xan hus mul icellula cell cycle. (A) Vege a i e g ow h. In he p esence o nu ien s cells mo e in a coo dina ed manne , o ming
swa ms. When swa ms make con ac wi h he p ey, cells pene a es he p ey colony and lyse he cells. (B) De elopmen al cycle. Upon s a a ion, cells mo ing
collec i ely ini ia e a de elopmen al p og am and exchange ex acellula signals as well as physical con ac signals o i s o m agg ega es and la e build
millime e -long up igh ui ing bodies illed wi h di e en ia ed, ep oduc i e and en i onmen ally esis an cells called myxospo es ( ounds cells), su ounded by wo
o he subpopula ions showing di ision o labo : a monolaye o aligned non- ep oduc i e pe iphe al ods (yellow od cells) and cells ha unde go al uis ic obliga o y
au olysis by p og ammed cell dea h (ligh b own od cells). Myxospo es ensu e su i al du ing s a a ion o desicca ion and can be dispe sed o o he en i onmen s
and ge mina e when nu ien condi ions amelio a e.
Fo bo h p eda ion and de elopmen , his myxobac e ium
uses sel -sec e ed ECM, in ica e social ne wo ks, and cell–
cell communica ion as he basis o i s mul icellula li es yle.
The ECM is a he e ogeneous mix o sec e ed uncha ac e ized
polysaccha ides, a small p o ein ac ion o unknown unc ion,
and ex acellula DNA (Kea ns e al., 2002;Bonne and Shimke s,
2006;Bonne e al., 2006;Cu is e al., 2007;Hu e al., 2012). ECM
is equi ed o sus aining M. xan hus mul icellula i y, no only
o main ain he in eg i y o cell g oups, which is impo an o
bio ilm o ma ion, cellula cohesion and connec ion o cells o he
subs a e, bu also because i pa icipa es in mo ili y and ui ing
body mo phogenesis (A nold and Shimke s, 1988a,b).
O e he en i e li e cycle, adjacen cells o M. xan hus a e also
in e connec ed by a ne wo k o ou e memb ane esicles (OMVs)
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Muñoz-Do ado e al. Myxobac e ia Mul icellula i y
FIGURE 2 | M. xan hus A and S mo ili y. (A) The edge o a M. xan hus swa m. Uppe ci cle, single cells (wi h A-mo ili y); bo om ci cle, g oup o cells (wi h
S-mo ili y). (B) Phase con as mic oscopy e ealing A-mo ili y-media ed ails obse ed a he leading edge. Mig a ion o o he cells h ough hese ails p omo es
he o ma ion o dense egions o aligned cells and a o s in ima e cell–cell con ac s. (C) P oposed ocal adhesion (FA) model o gliding mo ili y. The cy oplasmic,
inne memb ane and pe iplasmic componen s o he Agl–Gl mo ili y p o ein complex mo e along a helical ack (p o ided by cy oskele al p o eins) wi hin he cells.
A e his a icking, he complex engages he ou e componen s and hen he en i e complex adhe es o he subs a e ia ECM slime, o ming an FA ha allows he
machine y o push. The p o ein complexes ansloca e along he cellula ack, pushing he cell o wa d. (D,E) Componen s o he S-mo ili y sys em, ib ils and ype
IV pili (T4P). (D) Scanning elec on mic oscopy o he meshwo k o ib ils ha main ain cellula cohesion. (E) A omic o ce mic oscopy o T4P localized a he leading
cell pole. (F) P oposed model o S-mo ili y. T4P ancho s o he EPS p esen on neighbo ing cells and p opels he cell by cycles o ex ension, a achmen , and
e ac ion. The pic u es o he phase b igh A-mo ili y ails (B) and T4P (E) we e adap ed om Gloag e al. (2015) wi h pe mission o he au ho s, and om Pelling
e al. (2005) wi h pe mission; copy igh (2005) Na ional Academy o Sciences, USA. Mic og aph o he ib il ma e ial was kindly p o ided by L. J. Shimke s.
and ou e memb ane ubes (OMTs). Some au ho s conside ha
his a ay o lipid appendage-based b idges, which p o ides a
lexible connec ion be ween cells, migh play a unc ional ole
in cell- o-cell ans e o p o eins h ough ou e memb ane
exchange (OME) o in in e cellula signaling (Palsdo i e al.,
2009;Remis e al., 2014). The ne wo k o OMTs migh p o ide
an enla ged su ace a ea o me aboli e exchange, o e en connec
he pe iplasmic spaces o cells, al hough ano he possibili y is ha
hei occu ence in M. xan hus bio ilms only plays a s uc u al
ole by helping o physically bind cells oge he du ing social
beha io s (Remis e al., 2014) o by ac ing as nuclea ion si es
(Whi wo h, 2011). Rega ding OMVs, i has been p oposed ha
ee esicles would p o ide a mechanism o signal ansmission,
while OMV chains could media e di ec in e cellula con ac
c ea ing a i mly bonded mul icellula communi y. Pu i ied
OMVs con ain lipids, ucose, mannose, N-ace ylglucosamine,
and N-ace ylgalac osamine, and a small se o ca go p o eins
wi h hyd oly ic ac i i y and molecules associa ed wi h an ibio ic
ac i i y (Be leman e al., 2014;Remis e al., 2014). The ole o
OMVs in helping media e he killing o p ey o ganisms h ough
he deli e y o hese oxic p o eins o an ibio ics in coope a i e
p eda ion is unques ionable (Be leman e al., 2014;Keane and
Be leman, 2016), bu hey also con ain p o eins implica ed in
mo ili y, such as CglB, and Tgl ou e memb ane p o eins known
o be ans e able be ween cells (Hodgkin and Kaise , 1979).
Ou e memb ane exchange is a no el myxobac e ial
mechanism ha in ol es memb ane usion and he exchange
o la ge amoun s o ou e memb ane componen s among cells.
By using OME M. xan hus cells sha e cell con en o epai
damaged siblings, leading o ad an ageous consequences o
bo h he dono and he ecipien (Vassallo and Wall, 2016). The
po en ial ole o OME in o e coming cell damage and as a social
ool o make he ansi ions om unicellula ee-li ing cells
o mul icellula popula ions has been e iewed by Wall (2014)
and Cao e al. (2015). OME equi es di ec con ac be ween
wo o mo e cells, which need o be on a ha d su ace (Wei
e al., 2011). Al hough OMTs and OMVs could be in ol ed in
OME (Remis e al., 2014), i is mo e likely ha hese appendages
a e byp oduc s o OME o mo ili y (Duc e e al., 2013;Wei
e al., 2014). The cell su ace-associa ed p o eins T aA and
T aB a e he wo hos gene ic de e minan s implica ed in OME
(Cao e al., 2015). The cu en model o OME p oposed by
Cao e al. (2015) is ha M. xan hus cells physically in e ac
wi h one ano he and ha T aA–T aA in e ac ions o ce he
opposing memb anes in o con ac , p o oking a displacemen
o wa e be ween hem which ca alyzes ou e memb ane (OM)
usion. T aB migh also in e ac wi h T aA o o m a unc ional
complex o OM usion. Fusions a e ollowed by di usion
and exchange o OM con en s among neighbo ing cells. This
model o OM usion is u he suppo ed by he inding ha
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T aA/T aB unc ions as a cell–cell adhesion ac o (Vassallo e al.,
2015).
Myxococcus xan hus li es in a wide ange o en i onmen s,
bu i is p edominan ly ound in soils composed o a a ie y
o mic obial species and s ains (Reichenbach, 1999;Velice
e al., 2014). Howe e , o e he yea s myxobac e iologis s
ha e demons a ed ha he o ma ion o ui ing bodies is a
e y selec i e p ocess and ha each ui ing body consis s o
a single species. This means ha myxobac e ia a e able o
disc imina e be ween ela ed and non- ela ed indi iduals o
c ea e social g oups. Fu he mo e, se e al s udies ha e p o ided
e idence o he p esence in na u al popula ions o M. xan hus
o non-coope a ing o exploi ing chea e s, which a ise om
mu a ions and dis up o disable mul icellula coo dina ion
(Velice e al., 1998;Fiegna and Velice , 2005;K aeme and
Velice , 2011). Fo example, du ing coope a i e p eda ion chea s
may consume hyd olyzed p oduc s om he p ey wi hou he
p oduc ion o hyd oly ic enzymes. And he e is e idence ha
he p esence o socially de ec i e chea e s du ing ui ing body
o ma ion can educe g oup p oduc i i y ( o ins ance educing
po en ial spo e p oduc ion) o can e en d i e popula ions o
ou igh ex inc ion (Velice and Vos, 2009). Se e al mechanisms
may help M. xan hus o dis inguish sel om non-sel , hus
educing he isk o exploi a ion by chea e s and inc easing
he clonali y o ui ing bodies. Fo ins ance, he OME p ocess
is highly disc imina ing and i is able o selec i ely iden i y
kin as exchange pa ne s, which implies he abili y o non-
iden ical geno ypes o ecognize and exclude one ano he du ing
agg ega ion and ui ing body o ma ion (Vassallo e al., 2015).
Ano he mechanism ha p obably con ibu es o he en ichmen
o species wi hin ui ing bodies is he speci ic bac e iocin
o an ibio ic media ed killing (Smi h and Dwo kin, 1994).
Addi ionally, i has been sugges ed ha chemo ac ic esponses
o some a y acids, which a e en iched du ing de elopmen ,
play some ole in media ing sel - ecogni ion du ing ui ing body
o ma ion (Kea ns and Shimke s, 2001;Cu is e al., 2006;Lee
e al., 2011).
Nex , we will e iew he h ee bes cha ac e ized mul icellula
beha io s o M. xan hus: mo ili y, p eda ion, and de elopmen .
MOVING TOGETHER: ADVENTUROUS
AND SOCIAL MOTILITY, CELL
REVERSALS, AND RIPPLING
As men ioned abo e, M. xan hus mo es on su aces by using wo
complemen a y lagella-independen mo ili y o ms (Figu e 2A),
A-mo ili y and S-mo ili y. Bo h mo ili y sys ems, coo dina ed
in space and ime, no only acili a e he su ace mo emen
o indi idual cells, bu a e also essen ial o he expansion o
mul icellula swa ms, p eda ion and cons uc ion o mul icellula
ui ing bodies (Nan and Zusman, 2011).
A-mo ili y, o gliding mo ili y, d i es he mo emen o single
cells a he swa m edges. The A-mo ile cells glide slowly o explo e
new en i onmen s, change di ec ion h ough e e sal e en s, and
lea e behind ECM slime ails ha may be ollowed by o he
cells (Figu e 2B). The p ecise mechanism o A-mo ili y is no
comple ely known. Mo e han 40 genes ha e been implica ed o e
he yea s, and o hei p ecise ole and egula ion eade s a e
e e ed o e iews by Nan e al. (2014) and Islam and Migno
(2015). The e a e wo main heo ies p oposed o A-mo ili y.
The i s one, he “helical o o ” model, also called he “c awling
snail model,” conside s ha mo o s d i en by p o on mo i e
o ce (PMF) un along an endless looped helical ack d i ing
o a ion. Ro a ion depends no only on PMF bu also on an
in ac M eB cy oskele on. The gliding complexes a e o med by
se e al p o eins localized in he cy oplasm, inne memb ane,
and pe iplasm (Nan e al., 2010). Some o he gliding mo o s
en e ing in o he en al egion make con ac wi h su aces, p ess
he gliding su ace, de o m he cell en elope, and exe o ce
agains he polysaccha ide slime, p opelling he cell o wa d (Nan
e al., 2011, 2013). The second model is he “ ocal adhesion”
mechanism (Balagam e al., 2014;Islam and Migno , 2015), in
which i is p oposed ha he inne memb ane and pe iplasmic
componen s o he mul i-p o ein cell en elope complexes (Gl
complex), a ached o a PMF-d i en mo o (Agl complex), o m
he Agl-Gl appa a us ha mo es along he helical ack wi hin
he cell (Luciano e al., 2011;Ag ebi e al., 2015). Once he
a icking complexes engage he ou e memb ane componen s,
he en i e Gl appa a us becomes ixed ela i e o he subs a e
ia slime, o ming a ocal adhesion si e (Migno e al., 2007). The
con inual a icking o he ixed complex along he helical ack
p opels he cell o wa d (Figu e 2C).
Rega dless o he model, he ole o ECM in acili a ing
A-mo ili y is unques ionable and i has been demons a ed ha
i acili a es cell adhesion o he unde lying subs a e du ing
bac e ial su ace mo ili y (Duc e e al., 2012). This slime is
a sel -deposi ed suga polyme o unknown composi ion also
con aining OM ma e ials om cells ha may be deposi ed in
he slime ails du ing single cell mo ili y (Duc e e al., 2012,
2013). These ails begin a he lagging end o each cell and
leng hen as he leading end o he cell ad ances. Mig a ion o
o he cells h ough hese ails p omo es he o ma ion o dense
egions o aligned cells and a o s in ima e cell–cell con ac s
(Woglemu h e al., 2002;Yu and Kaise , 2007), con ibu ing o
he occu ence o well-o ganized pa e n ne wo ks in hese a eas
(Figu e 2B). In ac , i has been ecen ly p oposed ha gliding
slime plays an impo an ole in M. xan hus social beha io ia
s igme gic egula ion (Duc e e al., 2013). The a gumen o
his p oposi ion is ha slime is he physical mani es a ion o
he en i onmen (s imulus) ha con ibu es o he expansion
o he communi y, and con inuous a ic inc eases he amoun
o slime p oduced, esul ing in addi ional ec ui men o cells
mig a ing along hese ails (Gloag e al., 2015). Fu he mo e,
i has been pos ula ed ha his ail- ollowing beha io could
be simila o he social o ganiza ion o an s, which is media ed
by an ennae-bo ne chemosenso y sys ems (CSS; Kea ns and
Shimke s, 2001). Coinciden ally, one o he o aging phe omones
used by an s is 1, 2 diolein (dioleoyl glyce ol), a de i a i e o
he lipid phospha idyle hanolamine. I is known ha some a y
acids pu i ied om M. xan hus cell memb anes beha es as a
chemoa ac an s du ing de elopmen (Kea ns e al., 2001), so i
is likely ha lipid chemo axis is in ol ed in di ec ed mo emen s
h ough he ails. In ac , one abundan ECM-p o ein (FibA) is
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impo an o ac ic beha io s owa d lipids (Kea ns e al., 2002;
Bonne e al., 2006). Also, Duc e e al. (2013) ha e sugges ed
ha slime-embedded OM ma e ials o OMVs could con ain
signals ha would p omo e speci ic ecogni ion, acili a ing ail
ollowing and helping colony expansion. Recen ly, Balagam and
Igoshin (2015) ha e p oposed ha M. xan hus cells use a slime
ail- ollowing mechanism o o m cell clus e s simila o hose
desc ibed o P. ae uginosa (Zhao e al., 2013). They sugges ha
slime ails in luence he mo ili y o kin cells ha encoun e hese
ails, esul ing in hem ollowing and u he s eng hening he
ails.
S-mo ili y, o wi ching mo ili y, is cha ac e ized by he
swa ming mo emen o la ge cell g oups and i is s imula ed
by cell–cell p oximi y. This mo ili y is c ucial o bo h ui ing
body o ma ion (Shimke s, 1986a,b) and coope a i e p eda ion
(Pé ez e al., 2014). Fib ils, which a e pa o he ECM and
o m a he e ogeneous coa a ound he cell su ace (Figu e 2D),
he lipopolysaccha ide (Bowden and Kaplan, 1998), and he
e ac ile ype IV pili (T4P; Figu e 2E) a e he ex acellula
componen s associa ed wi h his ype o coope a i e mo ili y
(Kea ns and Shimke s, 2001). Fib ils a e hick, lexible s uc u es,
mainly composed o a small p o ein ac ion and a pa icula
exopolysaccha ide (EPS) ha con ains glucosamine, galac ose,
hamnose, and xylose (Behmlande and Dwo kin, 1994a,b;
Lu e al., 2005). They make up a malleable meshwo k ha
bundles adjacen cells oge he and main ains cellula cohesion
(Figu e 2F). They a e in ol ed in he ac i a ion o he S-mo ili y
mo o h ough cell p oximi y (Yang e al., 2000;Pelling e al.,
2005). EPS also exhibi s lub ica ing p ope ies ha alle ia e
he o ce gene a ion equi emen s on he lead cell, making
coo dina ed social mo ili y possible (Gibiansky e al., 2013).
This EPS also p o ides chemical signals o guide he wo
mo ili y sys ems (Kea ns and Shimke s, 2001;Duc e e al., 2013).
T4Ps loca ed a he leading cell pole ancho hemsel es o he
ca bohyd a e po ion o he EPS p esen on neighbo ing cells (o
on slime ails le by A-mo ile cells) and p opel he cell by cycles
o ex ension, a achmen and e ac ion (Figu e 2F) (Wall and
Kaise , 1999;Ske ke and Be g, 2001;Li e al., 2005;Mau iello
e al., 2010;Chang e al., 2016). To e e se di ec ion, bac e ia
disassemble he T4P appa a us on one pole and eassemble i a
he o he one.
In he swa ms, cells a e cons an ly mo ing, in e ac ing wi h
one ano he , and e e sing hei di ec ion in a coo dina ed
manne . In ac , cell e e sals and coo dina ion o he wo
mo ili y sys ems a e needed o achie e he di ec ional mo emen
equi ed o cellula agg ega ion o o m ui ing bodies
(Mau iello e al., 2010). These pe iodical e e sal e en s a e
imed by a eedback oscilla o in ol ing he F z ( izzy p o ein)
signal ansduc ion cascade, a CSS also called he pacemake
(Migno e al., 2005;Leona dy e al., 2010;Kaise and Wa ick,
2011;Moine e al., 2014;Guzzo e al., 2015). The mechanism
by which he F z sys em egula es he iming o gliding e e sal
and he equency o swi ching h ough he small GTPase MglA,
i s cogna e GTPase-ac i a ing p o ein MglB, and he esponse
egula o RomR has been ecen ly cla i ied (Bulyha e al., 2011;
Kaime e al., 2012;Keilbe g and Søgaa d-Ande sen, 2014;Islam
and Migno , 2015;Nan e al., 2015). The F z sys em has also been
p oposed as a no el mechanism o coo dina ing cell mo emen
h ough cell–cell con ac (Mau iello e al., 2009). Mo eo e ,
Kaise and Wa ick (2014) epo ed ha he A-mo ili y p o ein
CglB o ms p o ein–p o ein con ac s ha may be he signal
equi ed o build M. xan hus swa ms and o synch onize he
pacemake s o he connec ed cells. In addi ion o he F z sys em,
mo ili y is also egula ed by o he CSSs (Ki by, 2009;Moine e al.,
2014), which sugges s ha mo ili y can be chemo ac ic (Zhang
e al., 2012b). O he e idence, such as ea men wi h a ac an
lipids o oxic compounds ha leads o changes in he e e sal
pe iods, suppo s ha hypo hesis (Kea ns and Shimke s, 1998).
In he p esence o cell deb is, pep idoglycan, o many o he
mac omolecules (Shimke s and Kaise , 1982;Sage and Kaise ,
1994;Welch and Kaise , 2001;Be leman e al., 2006;Pé ez e al.,
2014), M. xan hus cells o ganize hei mo emen in o acco dion-
like wa es (Figu e 3A), which look simila o ipples in wa e
(S e ens and Søgaa d-Ande sen, 2005;Sliusa enko e al., 2006).
Du ing ippling, each wa e c es oscilla es back and o h wi h
no ne displacemen , al hough indi idual cells change posi ion.
When wo wa es collide, cells in one wa e pene a e he opposing
wa e by one cell leng h, ollowed by cell e e sals. Expe imen al
and heo e ical s udies o ippling beha io indica e ha hese
mo ing pa e ns can be p oduced by a side- o-side signaling
be ween wo cells ha may cause one o he cells o e e se, by
physical in e ac ions ha cause he cell o locally align, and by an
in e nal biochemical oscilla ion sys em (Igoshin e al., 2001, 2004;
Sliusa enko e al., 2006;Zhang e al., 2012a).
Finally, mo ili y is also c i ical o he a o emen ioned OME.
In ac , he i s p o eins known o be subs a es o ans e by
OME a e he A-mo ili y p o ein CglB and he S-mo ili y p o ein
Tgl (Hodgkin and Kaise , 1979;Nudleman e al., 2005). La e ,
se e al in es iga ions ha e concluded ha al hough OM p o ein
exchange is no es ic ed o mo ili y p o eins (Wei e al., 2011;
Pa hak e al., 2012;Vassallo e al., 2015), a leas one pa ne
(ei he dono o ecipien ) needs o be mo ile (Dey and Wall,
2014;Cao e al., 2015). The ole ha mo ili y plays in OME has
no been cla i ied, al hough i mos likely acili a es he p ope
cell–cell alignmen s and con ac s ha lead o exchange, o i may
pa icipa e in inco po a ing OM ma e ials in o he slime polyme
when cells ollow he slime ails (Duc e e al., 2013;Wall, 2014).
KILLING AND FEEDING TOGETHER:
COOPERATIVE LYSIS AND GROUP
PREDATION STRATEGIES
Du ing ege a i e g ow h, M. xan hus can g ow as a sap ophy e
on dead o ganic ma e by decomposing deg adable polyme s
o p ey upon a a ie y o G am-nega i e and G am-posi i e
bac e ia, as well as ungi (Mo gan e al., 2010;Mülle e al., 2014;
Pé ez e al., 2016). This ac i i y is also a mul icellula p ocess and
he e iciency o i s eeding s yle seems o be densi y-dependen
(Rosenbe g e al., 1977). Al hough indi idual M. xan hus cells
a e able unde ce ain ci cums ances o ca ch p ey ollowing a
cell- o-cell a ack (McB ide and Zusman, 1996), he usual eeding
s a egy is coope a i e p eda ion (Pé ez e al., 2016). Howe e , i
is unknown whe he M. xan hus shows a cell densi y-dependen
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FIGURE 3 | Myxococcus xan hus mul icellula beha io s. (A) M. xan hus DK1622 coo dina ed mo emen s ( ippling) induced by Sino hizobium melilo i AK70
(SmAK70) du ing p eda ion. (B) OMV chains c yo ixed and isualized by ansmission elec onic mic oscopy. OMVs con ain mul iple hyd oly ic enzymes and
seconda y me aboli es indica ing an impo an ole in killing and lysis o p ey. (C) Scanning elec on mic og aphs o he in e ace DK1622 (Mx) e sus S ep omyces
coelicolo M45 (Sc) cells a e 96 h o incuba ion. The magni ied pic u e shows he in ense ECM connec ion be ween he a acking cells. (D) F on al a ack s a egy:
M. xan hus DK1622 (Mx) e sus a non-mucoid colony o S. melilo i 8530W (Sm8530W). (E) Wol pack a ack s a egy: M. xan hus DZ2 (Mx) e sus a mucoid colony
o S. melilo i AK21 (SmAK21). (F) M. xan hus DZF1 ui ing body o ma ion a e 72 h on s a a ion medium. (G–I) Scanning mic oscopy o M. xan hus DZF1 ui ing
body showing he ound spo es and he su ounding pe iphe al ods. (H,I) Wi hin he ui ing bodies, he myxospo es a e i mly bound oge he by a cohesi e ECM.
Pic u e (B) has been adap ed om Remis e al. (2014) wi h pe mission, copy igh 2013 Socie y o Applied Mic obiology and John Wiley & Sons L d.
gene ic exp ession o p eda o y enzymes o i , con e sely, hese
enzymes a e exp essed cons i u i ely. In he la e case, high
cell densi y would simply acili a e p eda ion by inc easing he
concen a ion o ex acellula ly ic ac o s (Be leman and Ki by,
2009).
The i s s ep in p eda ion in ol es M. xan hus mo ili y
because p eda o cells equi e close p oximi y o he p ey
(McB ide and Zusman, 1996). P eda o y g oups (Figu e 3C)
ac i ely swa m owa d he p ey using he wo mo ili y sys ems
desc ibed p e iously. The oles in p eda ion o he wo mo ili y
sys ems a e imp ecise, bu i seems ha bo h A- and S-mo ili y
engines a e equi ed o e icien p eda ion (Pham e al., 2005;
Be leman e al., 2006;Be leman and Ki by, 2009;Pé ez e al.,
2014). Con ac wi h p ey cells s imula es e e sals ha a e
esponsible o indi idual M. xan hus cells becoming apped in
p ey mic o-colonies un il p ey-cell lysis is comple e (Keane and
Be leman, 2016). Addi ionally, a highe cell densi ies, con ac
wi h he p ey also yields ippling beha io . Howe e , he ole
o ippling in p eda ion emains o be cla i ied. Un il ecen ly,
ippling was accep ed as a c i ical p eda o y beha io ha
se es o maximize p eda ion e iciency and nu ien sca enging
(Be leman e al., 2006, 2008). Ne e heless, ippling is no always
necessa y o p eda ion because i nei he helps o o e come he
physical and chemical ba ie con e ed by he p ey no imp o es
p ey lysis (Pé ez e al., 2014).
The a ack s a egy o M. xan hus seems o depend on
he na u e o he p ey. By s udying p eda ion on di e en
Sino hizobium melilo i s ains, i has been shown ha his
myxobac e ium can ollow wo p eda o y ac ics ha depend on
he p esence o he hizobial EPS galac oglucan. The s a egy used
by M. xan hus agains labo a o y s ains o S. melilo i ha lack
galac oglucan is iden ical o ha p e iously desc ibed o o he
p ey (Be leman e al., 2008). This s a egy esembles a on al
a ack (Figu e 3D), whe e g oups o p eda o s p og essi ely
pene a e he p ey colony and lyse he cells (Be leman e al., 2008;
Pé ez e al., 2011, 2014). The o he s a egy i s well wi h he
adi ional de ini ion o M. xan hus p eda ion s a egy, e e ed
o as wol -pack a ack (Figu e 3E). In his case, M. xan hus cells
su ound he p ey colony and ipple be o e killing and lysing he
ield-isola ed galac oglucan-holding S melilo i s ains (Pé ez e al.,
2014).
Du ing p eda ion, M. xan hus swa ms sec e e a ple ho a o
hyd oly ic enzymes, an ibio ics, and o he seconda y me aboli es
ha lyse he p ey cells, eleasing a pool o hyd olyzed p oduc s
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in o he ex acellula milieu, which a e consumed by he
myxobac e ia (Sudo and Dwo kin, 1972;Wenzel and Mülle ,
2009;Xiao e al., 2011;E ans e al., 2012). How M. xan hus
p o ec s i sel om lysis by i s own ex acellula diges i e
enzymes is unknown, bu i has been sugges ed ha he
ECM could play a p o ec i e ole, because no mu an s ailing
o p oduce any p opulsi e slime ha e been isola ed despi e
he e o s o di e en labo a o ies (Kaise , 2015). Molecules
associa ed wi h p eda ion and p ey nu ien s will bo h end o
a el away om he gene a ing cell, p o iding a chance o
exploi a ion by o he s and inc easing he dilu ion by di usion
(Whi wo h, 2011;Mendes-Soa es and Velice , 2013). In his
p eda ion s a egy, chea ing is a po en ial p oblem because
he p eda o s ains gene a e a publicly accessible esou ce,
which chea s migh consume a he expense o coope a i e
s ains (E ans e al., 2012). As men ioned abo e, M. xan hus
p oduces OMVs in la ge quan i ies (Figu e 3B) and hei ole
in mul icellula beha io is s ill unde esea ch (Whi wo h,
2011;Remis e al., 2014;Keane and Be leman, 2016). Howe e ,
p o eomics s udies o OMVs ha e demons a ed ha hey
con ain mul iple hyd oly ic enzymes and seconda y me aboli es
associa ed wi h an ibio ic ac i i ies (Kahn e al., 2010;Be leman
e al., 2014;Remis e al., 2014). Mo eo e , unc ional s udies also
indica e ha OMVs play an impo an ole in p eda ion (Remis
e al., 2014). The packaging o mul iple p eda o y molecules
wi hin he OMVs, which deli e he le hal cock ail o he p ey
cells, slows he anspo a e o ly ic ac o s away om he
immedia e icini y o he p oducing o ganism and educes he
isk o po en ial compe i ion o exploi a ion by chea s, inc easing
he p eda ion e iciency (Whi wo h, 2011;E ans e al., 2012;
Be leman e al., 2014).
The mul iplici y o ac i i ies and unc ions associa ed wi h
g oup p eda ion implies a conside able numbe o signal-
ansduc ion p ocesses o de ec ing and acking p ey, and o
coo dina ing all he me abolic pa hways in ol ed in neu alizing
and lysing he p ey, o which he up ake and inco po a ion in o
he myxobac e ial me abolism o he eleased nu ien s mus be
added. Al hough his social beha io was i s desc ibed 75 yea s
ago, mos o hese sys ems emain o be elucida ed. This is mainly
due o he ac ha mos esea che s ha e concen a ed hei
in e es on he de elopmen al cycle. Mo eo e , M. xan hus is
no an obliga e p eda o since i g ows well in a ich medium.
Consequen ly, s udies on p eda ion a e lagging a behind hose
o o he p eda o s such as Bdello ib io (Pé ez e al., 2016).
I is known ha his in e ac ion has some consequences o
he p ey. Fo ins ance, S. melilo i AK21 cells espond o he
app oaching myxobac e ia by p oducing EPS and e ea ing
(Pé ez e al., 2014). I is also known ha M. xan hus induces
he o ma ion o spo e- illed megas uc u es in B. sub ilis (Mülle
e al., 2015), and p oduc ion o an ibio ics and di e en ia ion
in S ep omyces coelicolo (Pé ez e al., 2011). These esul s
suppo he idea ha p eda o –p ey in e ac ion can inc ease
he p oduc ion o seconda y me aboli es and, consequen ly, co-
cul u e wi h he p ey may be a s a egy wo h conside ing in
bio echnology esea ch on he na u al p oduc s o myxobac e ia.
Many ques ions need o be answe ed in he nea u u e, such as
wha he eal ecological consequences o M. xan hus p eda ion
a e on na u al en i onmen s, how he p ey induces he p eda o y
enzymes o seconda y me aboli es in M. xan hus, which o he
na u al ba ie s besides he EPS galac oglucan de e mine he
p eda ion s a egy o he myxobac e ia, how p eda o s de ec he
p ey, why con ac wi h he p ey is necessa y o p eda ion, and
how p eda o s maximize nu ien up ake.
SURVIVING TOGETHER: DIVISION OF
LABOR, FRUITING BODY FORMATION,
AND INTRA-/INTER-CELLULAR
SIGNALING
When nu ien s become limi ed, he ege a i e sp ead o he
myxobac e ia is cons ained and he popula ion ini ia es a
de elopmen al p og am ha culmina es wi h he o ma ion o
mul icellula , spo e- illed ui ing bodies (Figu es 3F,G). F ui ing
body o ma ion equi es a solid su ace o allow mo ili y, a
h eshold popula ion densi y, ecogni ion a he cellula le el
o he nu ien downshi , and a complex se ies o in e - and
in acellula signaling ha p oceeds in dis inc mo phological
s ages sepa a ed in ime and space (Dioda i e al., 2008;Higgs
e al., 2014;Rajagopalan e al., 2014).
The i s signs o de elopmen a e de ec able a e 4–6 h
o s a a ion, when cells agg ega e o o m small agg ega ion
cen e s. O e he cou se o he nex se e al hou s, hese ini ial
oci may disin eg a e, me ge o inc ease in size o become
la ge agg ega es. Sho ly a e eaching he agg ega ion cen e
(6–12 h), hese cells show a coo dina ed sequence o h ee
highly cha ac e is ic mo phological changes, including o ma ion
o la ge in acellula lipid bodies, cellula mo phogenesis in o
sphe ical p espo e cells, and o ma ion o a hick, mul ilaye ed
spo e en elope. As he agg ega ion cen e s accumula e mo e cells,
hey e en ually become mound-shaped. By 24 h he agg ega ion
p ocess is comple e and each nascen ui ing body con ains
app oxima ely 105–106densely packed cells. Inside he ui ing
bodies, he ege a i e od-shaped cells unde go mo phological
and physiological di e en ia ion in o sphe ical myxospo es
(Figu es 3G,H). Spo e ma u a ion is inished app oxima ely 72 h
a e he onse o s a a ion. Wi hin he ui ing bodies he
myxospo es a e i mly bound oge he by he cohesi e ECM
(Figu es 3H,I), hence, upon ge mina ion, he whole popula ion
c ea es a new swa m (Dioda i e al., 2008).
The numbe o di e en cell ypes ha occu in a g oup can
be compa ed o he numbe o cas es in eusocial insec colonies,
in which he di e en g oup membe s specialize a di e en oles.
The o al numbe o cells in hose g oups is pe cei ed as one o he
ac o s ha con ibu es o and co ela es wi h g oup complexi y
(S assmann and Quelle , 2010;Fishe e al., 2013). As men ioned
abo e, he M. xan hus de elopmen al monoclonal popula ion
seg ega es in o one o h ee subpopula ions ha show di ision
o labo (Figu e 1): 10% o cells di e en ia e in o spo es ha a e
p oduced wi hin mul icellula ui ing bodies and a e esis an
o hea , desicca ion, and nu ien dep i a ion (O’Conno and
Zusman, 1991a); 30% o cells di e en ia e in o pe iphe al ods
(a pe sis e -like s a e) ha emain on he ex e io o he ui ing
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Muñoz-Do ado e al. Myxobac e ia Mul icellula i y
body (O’Conno and Zusman, 1991a,b); and he emaining cells
unde go lysis by PCD (Wi eman and Dwo kin, 1977;Na iya and
Inouye, 2008).
The complex cellula di e en ia ion om od-shaped
ege a i e cells in o ound spo es in ol es emodeling o he
cell en elope, he syn hesis o he igid spo e coa (Mülle e al.,
2012), he o ma ion o a wo-ch omosome complemen (Tzeng
and Singe , 2005), and he syn hesis o spo e-speci ic lipid
componen s (Ring e al., 2006). Du ing spo ula ion, M. xan hus
cells unde go massi e ep og amming o hei gene exp ession
pa e ns (Mülle e al., 2010;Higgs e al., 2014) and ex ensi e
me abolic ea angemen s. In acellula lipid bodies a e p obably
used o ul ill hese cellula me abolic equi emen s. In ac ,
lipid bodies g adually disappea du ing spo e ma u a ion un il
hey a e en i ely used up when he cells ha e comple ed he
di e en ia ion p ocess (Ring e al., 2006).
Pe iphe al ods a e a disc e e subpopula ion o cells ha mo e
a ound and be ween ui ing bodies scou ing o ood. I has
been p oposed ha hey ha e e ol ed o ake ad an age o low
le els o nu ien s which a e insu icien o ei he p omo e g ow h
o o induce he ge mina ion o he spo es inside he ui ing
bodies (O’Conno and Zusman, 1991a). Fo his eason, his
subpopula ion is conside ed o unc ion as pe sis en cells which
do no unde go cell di ision bu a e likely eady o espond o
any sudden inc ease in nu ien s (O’Conno and Zusman, 1991a;
Higgs e al., 2014). Re u ning o he example o insec colonies,
in he case o M. xan hus, hese s e ile cells could ep esen a case
o ex eme al uism, as happens wi h s e ile wo ke s in eusocial
insec s, sac i icing any oppo uni y o ep oduc ion in o de o
help o he s. Howe e , and al hough i s desc ibed as al uis ic
(Zaha i and Ral , 1984), many myxobac e iologis s conside ha
bo h spo ula ion and di e en ia ion in o pe iphe al ods a e in
ac wo di e en su i al s a egies which, combined, con e
M. xan hus wi h a mo e comple e esis ance o ad e se condi ions
(Shimke s, 1999;Kaise e al., 2010;Mau iello e al., 2010;Zhang
e al., 2012b). E en hough pe iphe al ods supe icially esemble
ege a i e cells (Figu es 3C,I), di e en analyses ha e shown ha
hese cells appea o become hype pilia ed, do no signi ican ly
accumula e ex acellula polyme ic subs ances, exp ess ma ke s
ha clea ly dis inguish hem om ege a i e cells, and exp ess
di e en genes om hose o spo ula ing cells (O’Conno and
Zusman, 1991a;Higgs e al., 2014). Pe iphe al ods, while
expe iencing he same s a a ion p ocess, do no o m lipid
bodies, a e unable o o m ui ing bodies, and do no di e en ia e
in o spo es (Hoiczyk e al., 2009). One model p oposed o explain
he di e en ia ion in o pe iphe al ods sugges s ha hey may
be p oduced by cells ha do no make su icien end- o-end
con ac s o e icien ly exchange he C signal (Julien e al., 2000).
A di e en model p oposes ha pe iphe al ods may a ise om
cells ha ail o accumula e su icien le els o he de elopmen al
ansc ip ional egula o s M pC and i s a ge F uA (Lee e al.,
2012).
The hi d ype o cell a e du ing de elopmen is PCD.
The onse o cell lysis immedia ely p ecedes, o is concomi an
wi h, he onse o agg ega ion, bu i likely con inues du ing
ma u a ion o he ui ing bodies, o p o ide nu ien s ha
allow spo e di e en ia ion. Some au ho s conside ha cell lysis
could also play a ole in agg ega ion (Lee e al., 2012). I is
s ill unknown whe he cells unde go an al uis ic PCD p ocess
o i i is a p oduc o in a-swa m compe i ion. Two di e en
mechanisms o PCD ha e been p oposed. One o hem in ol es
he p oduc ion o au ocides, cha ac e ized as a mix u e o a y
acids and phospha idyl e hanolamine ha pe meabilizes he cells
and ul ima ely leads o lysis (Va on e al., 1984, 1986;Gel an
e al., 1987). The o he hypo hesis is based on he oxin-an i oxin
sys em, consis ing o MazF ( oxin) and M pC (an i oxin; Na iya
and Inouye, 2008). I should be no ed ha some expe imen s
ha e demons a ed ha his la e mechanism does no unc ion
wi h all M. xan hus s ains (Lee e al., 2012;Boyn on e al.,
2013). The e olu ion and main enance o cell lysis as an al uis ic
and coope a i e p ocess is possible only in g oups o closely
ela ed indi iduals. Al hough he p oduc ion o public goods by
he lysis o he majo i y o cells bene i s he communi y, some
indi iduals can exploi his si ua ion by using nu ien s wi hou
con ibu ing owa d hei p oduc ion. Such indi iduals ha e a
i ness ad an age, as hey do no u ilize hei own esou ces,
ye hey enjoy he bene i s. This leads o an inc ease in he
numbe o hese social chea e s in he popula ion. Exploi e
popula ions compe e wi h cells ha coope a e and, e en ually,
he en i e social s uc u e will collapse as nu ien s will no
be a ailable a su icien le els (Cao e al., 2015; an Ges el
e al., 2015). Consequen ly, his p ocess equi es a mechanism o
disc imina e kin om non-kin ha could be media ed by OME
(Cao e al., 2015). By his sys em, cells ha belong o he same
aA ecogni ion g oup a e mu ually immune o bac e iocin-
media ed killing, whe eas cells om di e en ecogni ion g oups
a e able o kill each o he (Pa hak e al., 2013).
In addi ion o he di e en cell a es desc ibed abo e, phase-
a ia ion and cell clus e ing also play di e en oles du ing
de elopmen . M. xan hus unde goes phase a ia ion o p oduce
non-pu e yellow o an colonies, whe e bo h a ian s can
swi ch om one o he o he (Laue and Gill, 1994). Phase
a ia ion in M. xan hus a ec s swa ming, ex u e o he colony,
pigmen a ion, ui ing body o ma ion, and spo ula ion (Meise
e al., 2006). Du ing g ow h, wild- ype yellow a ian s (WTY)
accumula e a he colony edge and su ound he slowe swa ming
wild- ype an a ian s (WTT; Dziewanowska e al., 2014).
WTY cells accumula e DKxan hene, a seconda y me aboli e
ha con e s he cha ac e is ic yellow colo (Meise e al.,
2006), and he an ibio ic myxo i escin, which a e needed o
spo ula ion and p eda ion (Xiao e al., 2011). WTT cells, which
p oduce ele a ed le els o i on acquisi ion sys ems, ail o
o m ma u e ui ing bodies and also p oduce ewe spo es
(Fu usawa e al., 2011). Ne e heless, WTT cells con ibu e
disp opo iona ely o he popula ion o spo es, al hough he
p esence o yellow cells is necessa y since hey p o ide some
ac o (maybe DKxan hene o myxo i escin) ha he an
cells need in o de o p oduce iable spo es (Meise e al.,
2006). This mu ual dependence migh gua an ee hei su i al.
T ansc ip omic analyses o WTY and WTT cells ha e ini ially
e ealed ha less han 1% o he M. xan hus genome is de o ed
o his p ocess, wi h only 41 genes di e en ially egula ed
du ing phase a ia ion (Fu usawa e al., 2011). Fu he global
s udies wi h WTY, WTT and h ee an mu an s ha e aised his
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