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Dictyostelium morphogenesis
Cornelis J Weijer
During starvation-induced Dictyostelium development, up to
several hundred thousand amoeboid cells aggregate,
differentiate and form a fruiting body. The chemotactic
movement of the cells is guided by the rising phase of the
outward propagating cAMP waves and results in directed
periodic movement towards the aggregation centre. In the
mound and slug stages of development, cAMP waves
continue to play a major role in the coordination of cell
movement, cell-type-specific gene expression and
morphogenesis; however, in these stages where cells are
tightly packed, cell–cell adhesion/contact-dependent signalling
mechanisms also play important roles in these processes.
the soil leaf litter where they feed on bacteria and divide
by binary fission. Under starvation conditions up to several hundreds of thousands cells aggregate chemotactically to form a multicellular structure (the slug) that,
directed by light and temperature gradients, migrates to
the soil surface to form a fruiting body. The fruiting body
is composed of a stalk supporting a mass of spores. The
spores disperse and under suitable conditions germinate
to release amoeba, closing the life cycle. I review our
understanding of the signalling mechanisms coordinating
cellular behaviours responsible for pattern formation and
morphogenesis.
Addresses
Division of Cell and Developmental Biology, School of Life Sciences,
University of Dundee, Wellcome Trust Biocentre, Dundee DD1 5EH, UK
e-mail: [email protected]
The control of cell movement during
development
Current Opinion in Genetics & Development 2004, 14:392–398
This review comes from a themed issue on
Pattern formation and developmental mechanisms
Edited by Derek Stemple and Jean-Paul Vincent
0959-437X/$ – see front matter
ß 2004 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.gde.2004.06.006
Abbreviations
ACA aggregation stage adenylylcyclase
Dif
differentiation inducing factor
PIP3 Phosphatidyl-Inositol(3,4,5)-Phosphate
PkA
cAMP dependent protein kinase
RGS regulator of G protein signalling
Introduction
One of the central aims of the study of development is to
understand how distinct cellular behaviours (e.g. division,
differentiation, apoptosis and movement) are coordinated
in space and in time to result in reproducible pattern
formation and morphogenesis. Coordination of these
cellular behaviours requires extensive communication
between cells of different types and cells and their
environment. The social amoebae Dictyostelium discoideum,
a simple genetically tractable organism situated at the
threshold of single and multicellular organisms in the
evolutionary tree of life, is well suited for the study of
these interactions because its genome has been
sequenced and it is amenable to experimental manipulation through targeted gene disruption and replacement
[1]. Dictyostelium cells normally live as single cells in
Current Opinion in Genetics & Development 2004, 14:392–398
As Dictyostelium development occurs under starvation
conditions, only limited cell divisions occur during multicellular development. Morphogenesis primarily results
from the arrangement of differentiating cells in a regulative spatial pattern. Key questions are: which signals
guide the movement behaviour of thousands of cells
during development, and how do movement and differentiation interact?
Aggregation
Starvation induces changes in the gene-expression programme that result in the cells acquiring the ability to
produce, secrete and degrade cAMP [2,3]. Through the
expression of the cAMP receptor, the cells also acquire
the ability to respond chemotactically to cAMP gradients.
It has emerged that chemotaxis results from the polarisation of the cytoskeletal dynamics persistently along the
cAMP gradient. Unstimulated amoeboid cells are changing shape continuously by extension and retraction of
pseudodpods in all directions resulting in a random walk
[4]. In the presence of an external gradient of a chemoattractant such as cAMP, the cells persistently extend
successive pseudopods in the direction of rising cAMP
concentration while suppressing the extension of lateral
pseudopods, which results in an efficient movement up
the gradient.
Much current research is directed towards understanding
how cells detect cAMP gradients, polarise and move in
response to it. Pseudopod extension is driven by actin
polymerisation, which provides the driving force for
extension and simultaneous disassembly of the myosin
thick filaments in the cortex at the site of extension as
well as localised delivery of membrane and or proteins to
allow extension to occur [5,6,7]. Cells also need to pull
up their back end and suppress the extension of lateral
pseudopods which involves members of the myosin I
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Dictyostelium morphogenesis Weijer 393
family and is dependent on internal cAMP levels [8,9].
To move forward the cells must gain traction from the
substrate on which they are moving, which involves the
formation of multiple transient (10–20s) actin contact
sites that have been shown to transduce traction forces
to the substrate [10,11]. It appears that cells may
undergo alternating phases of actin-driven extension at
the front and myosin-driven contraction at the back [12].
Much work is directed towards the investigation of the
molecular mechanism resulting in the molecular mechanism underlying signal detection and its translation in
directed movement, and has been reviewed recently
elsewhere [6,13,14].
Aggregation is caused by periodic cAMP synthesis and
secretion by cells in an aggregation centre [15]. Detection
and amplification of this signal by surrounding cells
coupled with desensitisation of the cAMP-producing cells
results in the propagation of waves of cAMP from the
aggregation centre outward (Figure 1). These waves of
cAMP guide the chemotactically moving cells towards the
aggregation centre, where they accumulate into a threedimensional aggregate: the mound [16,17]. Initially, the
cells move towards the aggregation centre as individuals,
but after 10–20 waves have passed they form bifurcating
aggregation streams, in which the cells make head-to-tail
contacts via calcium-independent adhesion molecules,
contact site A and side-to-side contacts via a calciumdependent contact molecule (Dd cadherin) [18,19].
Stream formation is dependent on the localisation of
aggregation stage adenylylcyclase (ACA) in the rear of
the aggregating cells, resulting in polarised cAMP secretion from the back of the cells [20]. cAMP wave propagation can be observed indirectly at the population
level via the observation of propagating optical density
waves that are associated with the periodic surges in cell
movement of groups of cells in the direction of the cAMP
signal during the rising phase of the cAMP wave, or at the
individual cell level by following the localised translocation of PIP3 at the leading edge of the cell [21]. During
aggregation the cAMP signals propagate as target patterns
or spiral waves from the aggregation centre outward. Cells
stay polarised as long as the cAMP signal is rising in time.
However, upon passage of the wave, the chemotactic
response adapts, which prevents the cells from turning
Figure 1
(a)
(b)
(c)
(d)
Current Opinion in Genetics & Development
Dictyostelium development is controlled by propagating cAMP waves. These waves possess distinct geometries typical for the different
stages of development. The cAMP waves are detected indirectly as optical density waves associated with the chemotactic movement of the
cells in response to the cAMP waves. Groups of cells moving directly during the rising phase of the waves scatter more light than non-moving,
less polarised cells during the falling phase of the waves. (a) Spiral waves typical for the early aggregation phase, when the cells are still in a
monolayer on agar. (b) Waves in a streaming aggregate. In the body of the aggregate, multi-armed spiral waves rotates counter clockwise,
throwing off individual wavefronts that propagate from the centre outward to the periphery of the aggregate directing inward movement of the
cells. (c) Multi-armed waves in a mound. In this image, the waves rotate counter clockwise, directing the clockwise movement of the cells in the
mound. (d) A slug migrating from right to left, showing two optical density waves, indicated by arrows, that travel from left to right. These waves
direct the migration of the prespore cells in the direction of the tip from right to left.
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Current Opinion in Genetics & Development 2004, 14:392–398
394 Pattern formation and developmental mechanisms
around and chasing after the cAMP waves once they have
passed. Adaptation of the chemotactic pathways, involving depolarisation of the cells may involve activation of a
newly discovered RGS-domain containing kinase as well
as the activation of PkA [9,22]. The number of cells in
aggregation streams appears to be controlled by the local
concentration of a secreted extracellular high molecular
weight complex protein complex, counting factor, which
through modulation of movement and adhesion may
control the numbers of cells that stably migrate in an
aggregation stream [23,24].
Mound and slug formation
After the cells have aggregated, they form the hemispherical mound. Mounds are characterised by rotating waves
of cAMP that direct the counter-rotational periodic
movement of the cells. Cells start to differentiate into
prespore and prestalk cells during aggregation, on the
basis of physiological biases like nutritional state and cellcycle position at the time of starvation already present in
the population before aggregation [25,26]. As a result,
there is little correlation between the time of arrival in the
mound and differentiation fate and the emerging cell
types initially form a ‘salt and pepper’ pattern in the
mound. Some prestalk cells then sort out to form the tip
and the slug tip guides the movement of all other cells
thus acting as an organiser. The tip’s action as an organiser can be mimicked by the periodic injection of cAMP
pulses of the right frequency and duration [17], suggesting that the tip is a source of periodic cAMP waves, in
agreement with the fact that prestalk cells express ACA
and the extracellular cAMP phosphodiesterase pdeA
[27,28]. It is not known which signals control tip-cell
fate but it is becoming clear that to proceed from the
aggregate to the mound stage cell–cell adhesion and/or
contact start to play an important role.
Mutants defective in the putative single-pass transmembrane contact molecules lagC, lagD and cotC cannot
proceed beyond the aggregation stage and are defective
in tip formation [29]. Surprisingly, mutants in some of
the newly discovered nine pass transmembrane receptors
of the Phag family, shown to be essential for phagocytosis,
display severe defects in slug formation and culmination,
suggesting a possible role for these receptors in cell–cell
adhesion [30]. Sorting of prestalk cells towards the tip
requires the invasive movement of prestalk cells through
a tightly packed mass of other cells and most likely
involves differential cell adhesion. Sorting of prestalk
cells is facilitated by secretion of a disintegrin family
protein and deletion of this protein results in a delayed
sorting and defective cell-type specification, demonstrating that sorting and cell-type specification are tightly
interlinked [31].
In slugs, optical density waves can be seen to propagate
from the middle of the prestalk zone to the back, reflectCurrent Opinion in Genetics & Development 2004, 14:392–398
ing the periodic movement of the cells forward (Figure 1).
These optical waves are strictly dependent on the tip.
Cells in the tip often rotate perpendicularly to the direction of slug migration, especially when it is lifted from the
substrate. In the posterior part of the slug, the cells move
forward periodically and all cells move on average with
the speed of the whole slug. It has been shown that the
assumptions of cAMP wave propagation and chemotaxis
in response to these waves is, in principle, sufficient to
explain morphogenesis from single-cell via aggregation,
stream and mound formation to cell sorting and slug
formation. The interactions between cell-signalling and
cell movement can be described in a robust way by
relatively simple mathematical models. In one of these
models the cells are described as a viscous fluid that
moves in response to the cAMP waves generated in an
excitable manner by the cells. This model is able to
explain the formation of aggregation streams, resulting
in the formation of a hemispherical mound. With the
additional assumptions that the prestalk and prespore
cells that differentiate in the mound in a salt and pepper
pattern differ in two properties, their ability to relay the
cAMP signal and their ability to move chemotactically in
response to the cAMP signal it is possible to obtain cell
sorting, where the prestalk cells move to the top of the
mound form a slug, which falls over and migrates away
(Figure 2). It would appear that these processes are
sufficient to explain Dictyostelium morphogenesis up
to the culmination stage [32,33]. However, the situation is almost certainly more complex because strains
lacking the ACA can still form slugs when they overexpress the catalytic subunit of protein kinase A. The
suggestion is that either there exists an ACA-independent
mechanism to produce periodic cAMP signals (e.g. involving cAMP generation by other adenylylcyclases ACB
and/or ACG and the recently discovered cAMP-stimulated cAMP phosphodiesterase [34]) or that there exists
altogether different mechanisms that can control cell
movement, such as contact following [35]. The latter
mechanism does not, however, explain what directs the
movement of the cells in the tip. It is possible that the
slime sheath secreted by prestalk cells [36], which surrounds the slug as a ‘stocking’, may keep the cells
together and may also give some polarity to the slug
but its role, although presumably important, has not
yet been investigated in detail.
Differentiation
A major goal is to understand the relationship between
cell movement and the signals that control differentiation. These signals must be able to maintain the correct
proportion of the prespore and prestalk celltypes in an
environment of extensive cell movement and changes in
shape of the slug. In the slug, the different cell types are
arranged in a simple axial pattern: pstA (prestalk A) cells
in the tip, a band of pstO cells, prespore cells with
intermingled anterior-like cells and rearguard cells that
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Dictyostelium morphogenesis Weijer 395
Figure 2
t=15min
t=0min
t=40min
t=200min
t=30min
t=0min
t=60min
t=40min
t=250min
t=80min
t=80min
Current Opinion in Genetics & Development
Model calculations of wave propagation and cell movement from aggregation to slug migration using a hydrodynamic model in which the
cells are described as a viscous fluid that move in response to propagating cAMP waves generated in an excitable manner by the cells [32].
The top row depicts the aggregation up to the mound stage. The first image starts with the randomly distributed cells (yellow) that are organised
by a spiral wave of cAMP (purple). They form aggregation streams and finally a hemispherical mound [45]. The middle row shows cell sorting and
the formation of a slug. The mound consist of two cells types: 20% yellow prestalk cells and 80% green prespore cells. They are initially
randomly mixed. The cAMP waves (purple) organise the movement of the cells. The prestalk cells are more excitable and move more strongly in
response to a cAMP wave. They move towards the centre of the mound and up to form the tip. The separation of the cells feeds back on the
signal propagation resulting in the formation of a twisted scroll wave. This leads to an intercalation of the cells and an upward extension of the
slug [46]. The bottom row shows that a slug organised by a scroll wave can move [32].
are precursors of the basal disk in the back of the slug [37].
It seems evident that this requires adaptive signalling
dynamics but the signals and the details of their regulation are not understood in detail. cAMP pulses control
the expression of aggregation-stage genes necessary for
cAMP relay and cell–cell contact and can control prespore
cell specific gene expression in later development [2,3].
Prespore cells, in turn, produce DIF, which controls the
differentiation of pstO cells [37,38,39]. DIF spreads by
simple diffusion from the prespore zone in adjacent
regions where it controls the differentiation of prestalk
O cells and possibly rear guard cells, in agreement with
the fact that Dif-dependent pstO translocation of StatC is
seen in both zones [40]. Cells in the pstA zone express
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ACA and studies investigating the cAR1-dependent
nuclear translocation of the transcription factor statA have
shown that cAM P levels are high in the tip, whereas
cAMP levels are lower elsewhere in the slug [28,41],
compatible with the idea that all the prestalk cells in the
tip and only the anterior-like cells in the posterior part of
the slug relay the cAMP signal. It is not known what
maintains the expression of ACA in the cells in the tip and
in anterior-like cells, but it could involve signalling
through newly discovered orphan serpentine receptors,
as deletion of these receptors results in defective tip
formation [42]. The mechanisms of cell-type proportioning and detailed signal-transduction pathways to cell-type
specific gene expression still need to be resolved.
Current Opinion in Genetics & Development 2004, 14:392–398
396 Pattern formation and developmental mechanisms
The switch from migrating slugs to fruiting body formation (culmination) appears to be controlled by a fall in
ammonia concentration. The identification of several
ammonia transporters, some of which are expressed in
the very tip and when deleted lead to a slugger (slugs
that fail to culminate) phenotype, supports the importance of ammonia as a morphogen [43]. Ammonia
signals most likely through the histidine kinase DhkC
to the response regulator domain of the internal cAMP
phosphodiesterase RegA, which is a major determinant
in the control of intracellular cAMP levels [3,44]. High
ammonia is expected to result in activation of regA
and low internal cAMP levels. A drop in ammonia is
expected to result in a rise of intracellular cAMP and
stalk-cell differentiation.
The authors describe the premier site for Dictyostelium resources that
includes genome analysis and stock centre information.
2.
Iranfar N, Fuller D, Loomis WF: Genome-wide expression
analyses of gene regulation during early development of
Dictyostelium discoideum. Eukaryot Cell 2003, 2:664-670.
A comprehensive analysis of expression of 3000 unique ESTs
(expressed sequence tags) during development, showing the specific
developmental regulation of 172 genes. 125 genes were expressed in
response to extracellular pulses of cAMP. Three genes, carA (cAMP
receptor), gbaB (G protein Beta), and pdsA (secreted phosphodiesterase), were consistently expressed early in development in the absence of
cAMP pulses, they are necessary to get the cAMP oscillations going. PKA
was demonstrated to have a critical role in transducing the cAMP signal to
early gene expression. In the absence of constitutive PKA activity,
expression of later genes was strictly dependent on ACA in pulsed cells.
3.
Saran S, Meima ME, Alvarez-Curto E, Weening KE, Rozen DE,
Schaap P: cAMP signaling in Dictyostelium. Complexity of
cAMP synthesis, degradation and detection. J Muscle
Res Cell Motil 2002, 23:793-802.
4.
Soll DR, Wessels D, Heid PJ, Voss E: Computer-assisted
reconstruction and motion analysis of the three-dimensional
cell. Scientificworldjournal 2003, 3:827-841.
Conclusions
Multicellular Dictyostelium morphogenesis results from
the chemotactic movement of thousands of differentiating cells coordinated by propagating waves of the chemoattractant cAMP produced by these cells. The dynamical
interactions between the cAMP waves and the resulting
chemotactic movement of the cells is formally sufficient
to explain aggregation, stream and mound formation. Slug
formation and culmination require the emergence of
prespore and several prestalk cell types that show distinct
cAMP signalling and movement properties. Only prestalk
and anterior-like cells relay the cAMP signals while both
prestalk and prespore cells move chemotactically in
response to these signals. However, prestalk cells move
more effectively than prespore cells, resulting in cell
sorting. Many of the molecular details underlying the
polarisation response to cAMP gradients and the mechanisms of actual movement, cell–cell contact and differentiation are beginning to be uncovered. It would appear
that direct cell–cell contact mediated signalling will play
an important role in the modulation of these processes, as
is the case in higher organisms. Dictyostelium will thus,
besides being a system of choice to investigate the
molecular mechanisms underlying cell polarity and chemotaxis, be an excellent model system to investigate the
principles underlying multicellular tissue organisation
and cell-type proportioning.
Acknowledgements
We apologise to those whose work was not cited due to space
constraints. I want to thank Dirk Dormann and Bakhtier Vasiev for their
discussions. This work was supported by the Biotechnology and Biological
Sciences Research Council and the Wellcome Trust.
References and recommended reading
Papers of particular interest, published within the annual period of
review, have been highlighted as:
of special interest
of outstanding interest
1.
Kreppel L, Fey P, Gaudet P, Just E, Kibbe WA, Chisholm RL,
Kimmel AR: dictyBase: a new Dictyostelium discoideum
genome database. Nucleic Acids Res 2004,
32(Suppl):D332-D333.
Current Opinion in Genetics & Development 2004, 14:392–398
5.
Thompson CR, Bretscher MS: Cell polarity and locomotion,
as well as endocytosis, depend on NSF. Development 2002,
129:4185-4192.
A temperature-sensitive mutant in NSF (NEM sensitive factor), an essential component of membrane transport, shows that NSF is essential for
phagocytosis, membrane internalisation and cell movement. The cAMPinduced actin polymerisation (cringe response) is intact in the mutant at
the restrictive temperature, but the cells round up and stop translocation,
possibly due a defect in generating cell polarity.
6.
Merlot S, Firtel RA: Leading the way: directional sensing through
phosphatidylinositol 3-kinase and other signaling pathways.
J Cell Sci 2003, 116:3471-3478.
7.
Blagg SL, Stewart M, Sambles C, Insall RH: PIR121 regulates
pseudopod dynamics and SCAR activity in Dictyostelium.
Curr Biol 2003, 13:1480-1487.
This is the first piece of genetic evidence showing that PIR121 is involved
in the negative regulation of SCAR, which controls the activity of the
Arp2/3 complex and actin polymerisation. Pir121 null mutants show
excessive actin polymerisation and continuous splitting of pseudopds
implying important roles for SCAR in the control of actin polymerisation
during psuedopod formation.
8.
Falk DL, Wessels D, Jenkins L, Pham T, Kuhl S, Titus MA, Soll DR:
Shared, unique and redundant functions of three members of
the class I myosins (MyoA, MyoB and MyoF) in motility and
chemotaxis in Dictyostelium. J Cell Sci 2003, 116:3985-3999.
This study shows that members of the myosin I class of motor proteins are
necessary for suppression of lateral psuedopods and efficient chemotaxis during aggregation in natural waves of cAMP. MyoF in particular is
necessary for attaining an elongated shape during chemotaxis.
9.
Zhang H, Heid PJ, Wessels D, Daniels KJ, Pham T, Loomis WF,
Soll DR: Constitutively active protein kinase A disrupts
motility and chemotaxis in Dictyostelium discoideum.
Eukaryot Cell 2003, 2:62-75.
Cells expressing a constitutively active PkA are incapable of suppressing
lateral pseudopods and maintain an ovoid shape, resulting in inefficient
movement. They are incapable of moving in response to natural waves of
cAMP implying PkA activation in dismantling cell polaritity at the peak of
the wave.
10. Uchida KS, Yumura S: Dynamics of novel feet of Dictyostelium
cells during migration. J Cell Sci 2004, 117:1443-1455.
The authors show that cells periodically form small, localised and close
contacts with the substratum and that these contact points are rich in
filamentous actin. By correlating these actin-rich contact points with the
local deformations of an elastic substrate on which these cells move, it is
shown that these contact points are the places where the cell transmits
traction forces necessary for movement to the substrate.
11. Bretschneider T, Diez S, Anderson K, Heuser J, Clarke M,
Muller-Taubenberger A, Kohler J, Gerisch G: Dynamic actin
patterns and Arp2/3 assembly at the substrate-attached
surface of motile cells. Curr Biol 2004, 14:1-10.
Using TIRF (total internal reflection fluorescence) microscopy the authors
show that cells make short lived (7–10sec) Arp2/3-rich foci in a myosin-IIindependent fashion. These high-resolution experiments furthermore
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Dictyostelium morphogenesis Weijer 397
show that the Arp2/3/foci often induce waves of actin polymerisation
propagating through the cell in a wave-like fashion, showing that actin
polymerisation machinery operates far from equilibrium. The Arp2/3-rich
foci are observed not only in the leading edge but also in the middle of the
cell, implying that the actin cytoskeleton is remodelled continuously
everywhere in the cell. It appears likely that these foci are the same as
the actin-rich contact sites shown in [10] to coincide with the points of
transmission of traction forces to the substrate.
12. Uchida KS, Kitanishi-Yumura T, Yumura S: Myosin II contributes
to the posterior contraction and the anterior extension during
the retraction phase in migrating Dictyostelium cells.
J Cell Sci 2003, 116:51-60.
This paper shows conclusively that cells undergo alternating cycles of
extension and contraction and it correlates these behaviours with the
generation of traction forces showing that both extension and contraction
at the rear contribute to forward movement.
13. Devreotes P, Janetopoulos C: Eukaryotic chemotaxis:
distinctions between directional sensing and polarization.
J Biol Chem 2003, 278:20445-20448.
A clear review describing rivalling hypotheses for cell polarisation.
14. Postma M, Bosgraaf L, Loovers HM, Van Haastert PJ:
Chemotaxis: signalling modules join hands at front and tail.
EMBO Rep 2004, 5:35-40.
A review of current molecular insight in the mechanisms underlying
coordination of events at the leading and trailing edges of the cell during
chemotactic movement.
15. Kimmel AR, Parent CA: The signal to move: D. discoideum
go orienteering. Science 2003, 300:1525-1527.
16. Dormann D, Weijer CJ: Chemotactic cell movement during
development. Curr Opin Genet Dev 2003, 13:358-364.
17. Dormann D, Weijer CJ: Propagating chemoattractant waves
coordinate periodic cell movement in Dictyostelium slugs.
Development 2001, 128:4535-4543.
18. Harris TJ, Ravandi A, Awrey DE, Siu CH: Cytoskeleton
interactions involved in the assembly and function of
glycoprotein-80 adhesion complexes in dictyostelium.
J Biol Chem 2003, 278:2614-2623.
19. Wong E, Yang C, Wang J, Fuller D, Loomis WF, Siu CH: Disruption
of the gene encoding the cell adhesion molecule DdCAD-1
leads to aberrant cell sorting and cell-type proportioning
during Dictyostelium development. Development 2002,
129:3839-3850.
The cadA gene encodes the Ca2þ-dependent cell adhesion molecule
DdCAD-1, one of the major calcium-dependent adhesion molecules. It is
expressed soon after the initiation of development in Dictyostelium. Cells
that lack DdCAD-1 are able to complete development and form fruiting
bodies, but they make abnormal slugs, culmination is delayed by
6 hours, and the yield of spores is reduced by 50%. The proportion
of prestalk cells in cadA slugs showed a 2.5-fold increase over the
parental strain. This indicates that, in addition to cell–cell adhesion,
DdCAD-1 plays a role in cell-type proportioning and pattern formation.
20. Kriebel PW, Barr VA, Parent CA: Adenylyl cyclase localization
regulates streaming during chemotaxis. Cell 2003, 112:549-560.
Kriebel et al. show that Dictyostelium cells, like neutrophils, polarise in
response to uniform stimulation of cAMP, which is normally produced by
ACA. Furthermore, it shows that the posterior localisation of ACA in
aggregating cells is necessary for efficient stream formation most likely
because it leads to localised end-to-end signalling between cells in
aggregation streams.
21. Dormann D, Weijer G, Parent CA, Devreotes PN, Weijer CJ:
Visualizing PI3 kinase-mediated cell-cell signaling during
Dictyostelium development. Curr Biol 2002, 12:1178-1188.
In this paper, we show that cells in aggregation streams and mounds
show periodic PIP3 production at the leading edge and that this correlates with a surge in forward movement. Cells in slugs, however, appear to
be polarised permanently in the direction of slug migration and this
polarisation depends on close range cell–cell signalling or direct cell–
cell contact
22. Sun B, Firtel RA: A regulator of G protein signaling-containing
kinase is important for chemotaxis and multicellular
development in dictyostelium. Mol Biol Cell 2003, 14:1727-1743.
23. Tang L, Gao T, McCollum C, Jang W, Vicker MG, Ammann RR,
Gomer RH: A cell number-counting factor regulates the
www.sciencedirect.com
cytoskeleton and cell motility in Dictyostelium. Proc Natl
Acad Sci USA 2002, 99:1371-1376.
24. Brock DA, Ehrenman K, Ammann R, Tang Y, Gomer RH: Two
components of a secreted cell number-counting factor bind to
cells and have opposing effects on cAMP signal transduction in
Dictyostelium. J Biol Chem 2003, 278:52262-52272.
25. Huang HJ, Pears C: Cell cycle-dependent regulation of early
developmental genes. Biochim Biophys Acta 1999,
1452:296-302.
26. Araki T, Abe T, Williams JG, Maeda Y: Symmetry breaking in
Dictyostelium morphogenesis: Evidence that a combination of
cell cycle stage and positional information dictates cell fate.
Dev Biol 1997, 192:645-648.
27. Weening KE, Wijk IV, Thompson CR, Kessin RH, Podgorski GJ,
Schaap P: Contrasting activities of the aggregative and
late PDSA promoters in Dictyostelium development.
Dev Biol 2003, 255:373-382.
28. Verkerke-van Wijk I, Fukuzawa M, Devreotes PN, Schaap P:
Adenylyl cyclase A expression is tip-specific in Dictyostelium
slugs and directs StatA nuclear translocation and CudA gene
expression. Dev Biol 2001, 234:151-160.
29. Kibler K, Svetz J, Nguyen TL, Shaw C, Shaulsky G: A cell-adhesion
pathway regulates intercellular communication during
Dictyostelium development. Dev Biol 2003, 264:506-521.
The authors show that three single-pass transmembrane putative calcium-independent adhesion molecules comC, LagC and lagD are essential for the transition of development from the late aggregate to the mound
stage. Evidence is presented that these genes fall into a regulatory
network in which comC inhibits lagC and activates lagD expression, lagC
and lagD are mutually inductive, and the cell adhesion gene lagC is the
terminal node in this signaling network.
30. Benghezal M, Cornillon S, Gebbie L, Alibaud L, Bruckert F,
Letourneur F, Cosson P: Synergistic control of cellular adhesion
by transmembrane 9 proteins. Mol Biol Cell 2003, 14:2890-2899.
31. Varney TR, Ho H, Petty C, Blumberg DD: A novel disintegrin
domain protein affects early cell type specification and pattern
formation in Dictyostelium. Development 2002, 129:2381-2389.
32. Vasiev B, Weijer CJ: Modelling of Dictyostelium discoideum
slug migration. J Theor Biol 2003, 223:347-359.
We have shown through the development of a physico-chemical model
that cAMP wave propagation by prestalk and anterior-like cells and
chemotactic movement of both prestalk and prespore cells are sufficient
to explain slug formation and migration. In this model, the prestalk and
prespore tissues are described as two distinct incompressible viscous
fluids, that move in response to cAMP waves, produced and propagated
by the prestalk cells. By varying the dynamics of cAMP signalling, the
chemotactic responsiveness of the prestalk and prespore cells and the
cell–cell interactions as described by changes in tissue viscosity, it is
possible to analyse their influence on slug migration and shape.
33. Umeda T, Inouye K: Cell sorting by differential cell motility: a
model for pattern formation in Dictyostelium. J Theor Biol 2004,
226:215-224.
See annotation [32].
34. Meima ME, Weening KE, Schaap P: Characterization of a
cAMP-stimulated cAMP phosphodiesterase in Dictyostelium
discoideum. J Biol Chem 2003, 278:14356-14362.
35. Umeda T, Inouye K: Possible role of contact following in the
generation of coherent motion of Dictyostelium cells.
J Theor Biol 2002, 219:301-308.
36. Morrison A, Blanton RL, Grimson M, Fuchs M, Williams K,
Williams J: Disruption of the gene encoding the EcmA,
extracellular matrix protein of Dictyostelium alters slug
morphology. Dev Biol 1994, 163:457-466.
37. Maeda M, Sakamoto H, Iranfar N, Fuller D, Maruo T, Ogihara S,
Morio T, Urushihara H, Tanaka Y, Loomis WF: Changing patterns
of gene expression in dictyostelium prestalk cell subtypes
recognized by in situ hybridization with genes from microarray
analyses. Eukaryot Cell 2003, 2:627-637.
38. Thompson CR, Fu Q, Buhay C, Kay RR, Shaulsky G: A bZIP/bRLZ
transcription factor required for DIF signaling in Dictyostelium.
Development 2004, 131:513-523.
Current Opinion in Genetics & Development 2004, 14:392–398
398 Pattern formation and developmental mechanisms
A bZIP/bRLZ transcription factor is here identified as a central regulator of
all known Dif responses and the DimA null mutant phenocopies the DmtA,
Dif null mutant, in that it does not make PstO cells.
39. Kay RR, Thompson CR: Cross-induction of cell types in
Dictyostelium: evidence that DIF-1 is made by prespore cells.
Development 2001, 128:4959-4966.
40. Fukuzawa M, Abe T, Williams JG: The Dictyostelium prestalk cell
inducer DIF regulates nuclear accumulation of a STAT protein
by controlling its rate of export from the nucleus.
Development 2003, 130:797-804.
Shows that Dif directs tyrosine phosphorylation and nuclear accumulation of StatC (signal transducer and activator of transcription). The nuclear
accumulation of statC is controlled by the inhibition of StatC nuclear
export, as shown via cytoplasmic photobleaching of StatC–GFP in living
cells. The paper furthermore shows that StatC functions as a transcriptional activator in a stress-response pathway.
41. Dormann D, Abe T, Weijer CJ, Williams J: Inducible nuclear
translocation of a STAT protein in Dictyostelium prespore cells:
implications for morphogenesis and cell-type regulation.
Development 2001, 128:1081-1088.
We show by monitoring the nuclear translocation of statA, which is
dependent on the level of extracellular cAMP, that slug tips are regions
of high extracellular cAMP. The absence of nuclear translocation of
statA in prespore cells is the result of ambient levels of extracellular
cAMP in the prespore zone being too low to cause nuclear translocation
of StatA. An increase in extracellular cAMP concentration by injection of
cAMP in the extracellular space in the prespore region of the slug results
in rapid translocation of StatA in prespore cells. These findings are in
agreement with findings described in [28], where extracellular cAMP
was manipulated by ectopic expression of the aggregation stage
Current Opinion in Genetics & Development 2004, 14:392–398
adenylylcyclase (ACA) in prespore cells, resulting in nuclear translocation of statA in prespore cells. These results are compatible with the idea
that prestalk and anterior-like cells relay the cAMP signal and prespore
cells do not.
42. Raisley B, Zhang M, Hereld D, Hadwiger JA: A cAMP receptor-like
G protein-coupled receptor with roles in growth regulation
and development. Dev Biol 2004, 265:433-445.
43. Follstaedt SC, Kirsten JH, Singleton CK: Temporal and spatial
expression of ammonium transporter genes during growth
and development of Dictyostelium discoideum.
Differentiation 2003, 71:557-566.
Three ammonium transporters (amtA–C) are identified in Dictyostelium,
which may play a role in ammonia signaling, in addition to physically
altering the levels of ammonia within cells. AmtC is expressed in the most
anterior tip of fingers and slugs, corresponding to cells that mediate
ammonia’s effect on the choice between slug migration and culmination.
Indeed, amtC null cells have a slugger phenotype suggesting that it may
play a role in this choice.
44. Singleton CK, Zinda MJ, Mykytka B, Yang P: The histidine kinase
dhkC regulates the choice between migrating slugs and
terminal differentiation in Dictyostelium discoideum.
Dev Biol 1998, 203:345-357.
45. Vasiev B, Siegert F, Weijer CJ: A hydrodynamic model for
Dictyostelium discoideum mound formation. J Theor Biol 1997,
184:441.
46. Vasiev B, Weijer CJ: Modeling chemotactic cell sorting during
Dictyostelium discoideum mound formation. Biophys J 1999,
76:595-605.
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