1 Developmental Biology Program, Institute of Biotechnology, PO Box 56,
FIN-00014, University of Helsinki, Helsinki, Finland
2 Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY
10595, USA
* Author for correspondence (e-mail: isalazar{at}mappi.helsinki.fi)
Accepted 29 January 2003
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SUMMARY |
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Key words: Induction, Pattern formation, Morphodynamic development, Morphostatic development, Morphogenesis, Tooth, Brain, Limb, Evolution, Genetic networks
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INTRODUCTION |
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Organismal development is enabled by developmental mechanisms. A developmental mechanism is understood in this paper as gene product interactions and changes in cellular behaviors (such as mitosis, apoptosis, secretion of molecular signals, cellular adhesion, differentiation, and so forth) that are required for and cause the formation of a particular arrangement of cell states in three-dimensional space (i.e., a `pattern'; we reserve the word `form' for the spatial arrangement of cells without considering their state). In formal terms the development of an organism can be described as transformation from one set of patterns to another set of patterns and here we aim to highlight the basic logic of the developmental mechanisms underlying these pattern transformations.
Causal explanations of pattern formation in an embryonic primordium require knowledge of all the genes, epigenetic determinants (that is, surrounding cell arrangements and other microenvironmental conditions in the embryo), and their interactions necessary for generating such a pattern from a previous pattern. In practice, causality can be inferred by testing how well a developmental mechanism predicts the `variational' properties the range of potential morphological outcomes.
It is common in theoretical discussions of development to distinguish two
components of pattern formation (Wilkins,
2001). First, pattern formation through cell-cell signaling
mechanisms (we will refer to these as inductive mechanisms)
establishes cells with different states and different spatial relationships by
signaling in two and three dimensions in developing planar and solid tissues,
respectively. Second, mechanisms that use cell behaviors other than signaling
(we will refer to these as morphogenetic mechanisms) act on the
previously established pattern to cause the formation of three-dimensional
tissues and organs. As described in detail below, morphogenetic mechanisms
change the spatial distribution of cells without changing cell states.
Morphogenetic and inductive mechanism act at all stages of development. Inductive mechanisms are generally implicated in developmental changes that produce new patterns. Because induction is a prerequisite for development to proceed no particular attention is normally paid to the order in which inductive and morphogenetic mechanisms function. We suggest, however, that the relative timing, including possible coincidence, of inductive and morphogenetic mechanisms can have major consequences for developmental dynamics and the range of potential morphological outcomes, and is therefore of central importance for the understanding of both development and morphological evolution. In fact the terms `pattern', `pattern formation' and `morphogenesis' are often used in different and not always explicit ways. In this article, we define these terms in a way that does not make assumptions about how inductive and morphogenetic mechanisms interrelate in producing developmental change.
A key aspect of our treatment is the introduction (or rather appropriation)
of the term `morphodynamic' (distinguished from `morphostatic') to
characterize complex developmental mechanisms in which inductive and
morphogenetic mechanisms interact with one another in a reciprocal fashion.
The need for new concepts to bring order to the complexities of morphogenesis
was anticipated by earlier investigators such as the cell biologist Paul
Weiss, whose influential textbook of developmental biology was first published
under the German title Morphodynamik
(Weiss, 1926) and later
published in English as Principles of Development
(Weiss, 1939
). The
mathematician René Thom used the allied phrase "dynamics of
forms" in his topological treatment of embryogenesis and human biology
Structural Stability and Morphogenesis
(Thom, 1975
).
In the following sections we briefly review and classify the main types of
developmental mechanisms for which there is experimental evidence. As noted,
these can be characterized as basic mechanisms that employ only one or few
cell behaviors. Although our main objective is to explore the ramifications of
the heretofore overlooked morphostatic/morphodynamic distinction, we also
emphasize that efforts to formulate useful computational models of
developmental and evolutionary-developmental scenarios
(Hunding et al., 1990;
Mjolsness et al., 1991
;
Drasdo and Forgacs, 2000
;
von Dassow et al., 2000
;
Solé et al., 2000
;
Salazar-Ciudad et al., 2001a
;
Salazar-Ciudad et al., 2001b
)
will benefit from an accurate schematization of the full range of
experimentally confirmed developmental mechanisms.
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A REPERTORY OF BASIC DEVELOPMENTAL MECHANISMS |
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Asymmetric mitosis
Nearly all cells exhibit some kind of internal polarity causing gene
products or mRNAs to be distributed into different parts of a cell and become
incorporated into different daughter cells. The difference with the previous
mechanism is that here gene products or mRNAs are asymmetrically transported
to the future daughter cells while the mother cell is dividing, whereas in the
previous case no transport occurs during cleavage. A non-random pattern
results from asymmetric mitosis if cells take invariable positions after
division. Asymmetric mitosis is found in the early cleavage divisions of many
groups such as nematodes (Bowerman and
Shelton, 1999), mollusks
(Collier, 1997
), ctenophores
(Freeman, 1976
) and annelids
(Bissen, 1999
), but also in
later processes such as the formation of the central nervous system of
Drosophila (Doe and Bowerman,
2001
). In some cases, cell signaling may also determine which
daughter cell will receive which set of factors
(Doe and Bowerman, 2001
).
Internal temporal dynamics coupled to mitosis
Temporally cyclical expression of genes can produce a pattern if
oscillation becomes decoupled from cell division. Cyclical gene expression can
result from closed chains of molecular events that trigger each other in a
sequential fashion (`dominoes') or by genetic networks with inherent
oscillatory dynamics (`clocks') (Murray
and Kirschner, 1989). If, when cells divide, one of the daughter
cell stops or resets its temporal dynamics, then cells can acquire different
states depending on the time of their mitosis. As in the case of asymmetric
mitosis, an invariable positioning of cells is required in order to generate
non-random patterns. This mechanism has been proposed for the segmentation of
hirudean leeches, oligochaetes (Weisblat
et al., 1994
), short germ-band insects
(Newman, 1993
;
Salazar-Ciudad et al., 2001b
),
the somitogenesis of vertebrates (Newman,
1993
) and in the formation of morphological structures, such as
the limb and the tail, involving `progress zone' growth
(Duboule, 1995
). Experimental
evidence for this mechanism is still limited, but in vertebrates it has been
shown that expression of genes involved in somitogenesis exhibit oscillatory
behavior (Maroto and Pourquié,
2001
).
Inductive mechanisms
Cells can affect each other by secreting diffusible molecules, by means of
membrane-bound molecules or by chemical coupling through gap junctions. A
large number of mechanisms which use only these developmental functions are
capable of pattern formation. In inductive mechanisms tissue pattern changes
as a direct consequence of changes in cell state. This, in turn, is due to the
processing or interpretation of signals sent by other cells. In certain cases,
inductive pattern formation assumes a simple form, that is, one cell or tissue
type will change the state of another cell or tissue type from what it would
have been without the interaction, with no morphological consequence following
directly from this. In other cases a morphological consequence accompanies, or
follows closely upon, the change in state of the induced target cells. Since
our aim here is to show how such composite inductive-morphogenetic
mechanisms comprise highly divergent categories of developmental mechanisms,
we will focus initially on the simple case without immediate morphological
consequences.
Examples of simple inductive mechanism are mesendoderm induction in
amphibians by maternal factors produced by the Nieuwkoop center
(Harland and Gerhart, 1997),
and the short-range signaling hierarchy in the echinoid blastula, in which the
oral-aboral axis is established by signaling from the micromere tier to the
macromeres, which, in turn, signal the mesomeres
(Davidson et al., 2002
). Other
examples include generation of the gradient patterns of gap gene products in
the Drosophila syncytial blastula induced by the patterns of maternal
gene products, and the subsequent induction of striped patterns of pair-rule
gene products, based on these gap patterns
(Rivera-Pomar and Jackle,
1996
).
Many basic inductive mechanisms appear to be based on hierarchic
genetic networks (Salazar-Ciudad et al.,
2000). In such networks a territory (or a single cell) may signal
another, and this second may respond to such signaling by sending a signal
back. This back-signal, however, does not affect the signaling rate or
capacity of the first territory. Inductive mechanisms can also be based on
emergent genetic networks in which cells or territories send signals
in a way that is affected by neighboring cells' responses to such signals
(Salazar-Ciudad et al., 2000
).
Emergent genetic networks, which comprise reaction-diffusion mechanisms
(Turing, 1952
;
Meinhardt and Gierer, 2000
;
Salazar-Ciudad et al., 2001a
)
but also include other mechanisms in which cells affect one another in
reciprocal ways, such as those used in the Notch-Delta signaling system (for
details, see Salazar-Ciudad et al.,
2000
), have been suggested to underlie limb skeletal patterning
(Newman and Frisch, 1979
;
Miura and Shiota, 2000a
;
Miura and Shiota, 2000b
),
pigment patterning in the butterfly wing
(Nijhout, 2001
), feather bud
spacing in avian skin (Jiang et al.,
1999
; Prum and Williamson,
2002
) and fish colour patterns
(Kondo and Asai, 1995
).
Theoretical studies have indicated that hierarchical and emergent mechanisms
together exhaust the possibilities for simple inductive mechanisms
(Salazar-Ciudad et al., 2000
),
and have explored their variational properties
(Salazar-Ciudad et al.,
2001a
).
Morphogenetic mechanisms
A number of patterning mechanisms use cellular behaviors other than
signaling (although signaling may have been active at a prior stage). These
mechanisms alter pattern by affecting form. This can be defined as a mechanism
that changes the relative arrangement of cells over space without affecting
their states.
Directed mitosis
Intracellular or extracellular signals can affect the direction of the
mitotic spindle. Once the mitotic spindle assumes a set direction, new cells
are forced to be positioned at specific places. The central nervous system of
Drosophila, for example, forms by the dorsally directed budding of
presumptive neuroblasts from the ectoderm (Broadus and Spana, 1999). This
produces two cordons of neuroblasts that extend longitudinally in the ventral
part of the embryo. Asymmetric mitosis and inductive signals are involved in
determining which cells will become neuroblasts, but their localization is
ultimately determined by the control of mitotic spindle orientation. External
inductive signals have been shown to direct the mitotic spindle in the first
divisions of C. elegans
(Goldstein, 2000) and in the
leech (Bissen, 1999
). In
ctenophores the form of the whole blastula is attained through precise
regulation of the orientation of the mitotic spindle
(Freeman, 1976
).
Differential growth
A change in a pattern can be produced if, in a previously existing pattern,
cells with different states divide at different rates. The new pattern depends
on the previous pattern, the relative rates and directions of mitosis and on
other epigenetic factors such as the adhesion between cells and the influences
of surrounding matrices. One such example is the establishment, maintenance,
and waning of the growth plate during the formation of long bones in
vertebrates (Sandell and Adler,
1999).
Apoptosis
A pattern can be transformed into another if some of the cells undergo
apoptosis. Apoptosis can be strictly dependent on a cell's lineage, or
triggered by interaction, or abrogation of interaction, with surrounding cells
(Meier et al., 2000). Although
apoptosis, in the first instance, is a cell autonomous function, the
patterning consequences depend on the existence and arrangement of surrounding
cells. The associated developmental mechanism is thus morphogenetic
rather than cell autonomous. A wide range of developmental processes are
dependent on apoptosis, including the outflow tract and valves of the heart
(Poelman et al., 2000), development of neural circuitry in the brain
(Kuan et al., 2000
), and
freeing up of the digits during vertebrate limb development
(Chen and Zhao, 1998
). In
particular, it has been shown that the final shape of the interdigital
membranes depends on the amount of apoptosis in such membranes
(Gañan at al.,
1998
).
Migration
Cells can rearrange their relative positions without changing their states
simply by migrating. Migration can be directionally random, random but speeded
up by an ambient chemical signal (`chemokinesis'), or have a preferred
direction in relation to a chemical gradient (`chemotaxis') or an insoluble
substrate gradient (`haptotaxis'). While mesencephalic neural crest cell
migration in the mouse appears to be controlled in part by a chemotactic
response to members of the FGF family of growth factors
(Kubota and Ito, 2000),
migration of trunk neural crest cells in the chicken appears to depend on more
random dispersal mechanisms (Erickson,
1988
). The migration of premuscle cells into the developing
vertebrate limb is regulated by both chemokinetic and chemotactic responses to
hepatocyte growth factor (Lee et al.,
1999
). Regardless of the migratory mechanism, specificity of
outcome will also, in general, be controlled by the adhesive environment of
the destination sites (Lallier et al.,
1994
).
Differential adhesion
Cell adhesion is the defining property of multicellular organisms. It is an
indispensable requirement for cell shape, differentiation and migration. A
large, but limited number of pattern changes can be produced in tissues by
constituent cells expressing different adhesion molecules or the same
molecules at different levels. Hence, differential adhesion can cause
subpopulations of cells to sort out into distinct groups. In a solid
epithelioid tissue compartments may have straight or curved boundaries, or
engulf or be engulfed by each other, depending on the magnitude of the
adhesive differences (Steinberg,
1996). If adhesion is expressed nonuniformly on the surfaces of
individual polarized cells, interior spaces or lumens can form in solid
tissues (Newman and Tomasek,
1996
). In planar epithelia, polar expression of adhesion along
with differential adhesion of subpopulations can produce invaginations,
evagination, placodes and the formation of cysts
(Newman, 1998
). Convergent
extension, a reshaping of tissue masses during gastrulation which involves
cell intercalation (Keller et al.,
2000
) can also be accounted for by energy minimization in
populations of anisotropic cells (Zajac
et al., 2000
), particularly those that exhibit `planar cell
polarity' (Mlodzik, 2002
). In
well-studied cases some of these processes also involve mitosis or cell
contraction, but this is not strictly required. Differential adhesion and cell
polarity or anisotropy are in principle sufficient to achieve these
morphological outcomes. Altered adhesion is also the final step in the set of
transformations known as epithelial-mesenchymal and mesenchymal-epithelial
conversions. An example of the first occurs during development of the neural
crest (Le Douarin and Kalcheim,
1999
) and the second occurs during the formation of the kidney
tubules (Davies and Bard,
1998
).
Contraction
Individual cell contraction mediated by actin-myosin complexes can have
morphogenetic effects on neighboring cells and the tissue as a whole.
Contraction of tissues during development is thought to trigger shape change
and determine the character of the morphological outcomes
(Beloussov, 1998). Contraction
is propagated in epithelial tissues by direct physical attachment and in
mesenchymal tissues by the extracellular matrix. In a planar epithelium
contraction can also lead to buckling, and thus invagination or evagination
(Newman, 1998
). A recent study
considered the role of myocardial contraction in trabeculation in the
developing heart (Taber and Zahalak,
2001
).
Matrix swelling, deposition and loss
The cells of mesenchymal and connective tissues are surrounded and
separated by semi-solid or solid extracellular matrices. Changes in pattern
may be accomplished by increased hydration or swelling of a preexisting
matrix, increase in the amount of matrix separating the cells, or matrix
degradation. During development of the avian eye, the primary corneal stroma
swells in anticipation of its invasion by mesenchymal cells from the periphery
(Hay, 1980). This swelling has
been found to be controlled by tissue-specific, developmentally regulated
proteolysis of collagen IX (Fitch et al.,
1998
). Vertebrate limb chondrogenesis is an example of a
developmental process in which cellular rearrangement occurs as a result of
matrix deposition. Here there is dispersal of newly differentiated
chondrocytes within compact precartilage mesenchymal condensations and
consequent flattening of more peripheral mesenchyme into a perichondrion
(Hall and Miyake, 2000
).
Developmentally regulated matrix degradation, particularly of basement
membrane components, has the capacity to alter cell positional relationships.
Such changes are important in triggering new developmental events, for example
during sea urchin gastrulation (Vafa et
al., 1996
) and mammary gland morphogenesis
(Werb at al., 1996
).
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VARIATIONAL PROPERTIES OF THE BASIC DEVELOPMENTAL MECHANISMS |
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The variational properties of inductive mechanisms are discussed in
previous work (Salazar-Ciudad et al.,
2000; Salazar-Ciudad et al.,
2001a
). In essence, for the same amount of molecular variation
inductive mechanisms that contain a self-organizing component (`emergent')
typically produce more, and more complex, patterns than those that are
organized in a hierarchic fashion. In contrast to emergent mechanisms, in
which similarly constructed networks can generate very different patterns,
hierarchic mechanisms based on similar gene networks tend to generate patterns
that are similar to one another. Furthermore, complex patterns are difficult
to attain by hierarchic networks: in general, a hierarchic network capable of
producing a particular complex pattern would have to contain many more genes
and many more connections among them than an emergent network capable of
producing that pattern. These characteristics entail a more complex
relationship between phenotype and genotype in emergent mechanisms than in
hierarchic ones.
The variational properties of morphogenetic mechanisms have also been
widely discussed (Newman and Müller,
2000; Beloussov,
1998
; Alberch,
1982
; Oster and Alberch,
1981
). Morphogenetic mechanisms have a strong dependence on the
epigenetic context and changes in their molecular components or
microenvironments can have dramatic phenotypic effects. Morphogenetic
mechanisms, furthermore, often involve mechanical interactions between cells
and extracellular matrix. This implies that their outcomes depend on such
aspects of the developing system as the material (e.g., viscoelastic,
cohesive) properties of cells and extracellular matrix or their spatial
distribution (Newman and Müller,
2000
). In particular, tissues and extracellular matrices may
respond very differently to stresses depending on their form and the relative
orientation of the stresses to which they are subjected
(Beloussov, 1998
).
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COMBINING INDUCTIVE AND MORPHOGENETIC MECHANISMS |
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Implications at the cellular level
How cells respond internally to received signals in order to coordinate
their behaviors and produce the coherent pattern transformations discussed
above is a current area of interest in developmental biology. It is therefore
significant that morphodynamic and morphostatic mechanisms have different
implications for the internal logic used by cells to produce patterns. During
development cells are constantly sending and receiving molecular signals. The
network of transcription factors and transduction molecules within a cell
integrates the cell's previous history with received signals and then alters
cell behaviors. The transduction of received molecular signals elicit, in
target cells, the production of signaling, structural or catabolic molecules
(Montross et al., 2000;
Carnac at al., 1996
), apoptosis
(Su et al., 2001
;
Barlow et al., 1999
;
Ferrari et al., 1998
), mitosis
(Hu et al., 2001
;
Cecchi et al., 2000
;
Salser and Kenyon, 1996
)
expression or repression of cellular receptors
(Panchision et al., 2001
;
McPherson et al., 2000
) and/or
changes in the contractility or adhesivity of cells
(Wacker et al., 2000
;
Lincecum, 1998; Packer et al.,
1997
; Jones et al.,
1992
).
In morphostatic mechanisms once a cell has attained a new cell state through signaling (a state that depends on the received signal and on the cell's previous developmental history) it follows an autonomous, temporal program of behavioral changes that is specified, mainly, by the transcriptional factors it now expresses. Since the spatial configuration of signals can be established by emergent as well as hierarchical inductive mechanisms, the hallmark of the morphostatic mechanism is not the absence of reciprocal cell interactions in generating this configuration, but rather the causal separation between setting up the signals and the cell behavioral response to such signals.
The positional information metaphor
(Wolpert, 1969;
Wolpert, 1989
), in which
cells acquire their fates as a result of exposure to different concentrations
of a signaling molecule, is one example of a morphostatic mechanism. Different
developmental outcomes arise not from differences in the mechanisms by which
genetic territories attain their forms, but in the different interpretation of
this positional information. The nature of this interpretation is unspecified,
but, as Wolpert explicitly proposes morphogenetic mechanisms act after and
subordinately to inductive mechanisms
(Wolpert, 1989
), it is clear
that interpretation implies the following of some sort of autonomous genetic
program. The spatiotemporal coordination of cell behaviors required in
development is assumed to be the outcome of the autonomous use, by each cell,
of its own genetic program specified though an inductive signaling
environment, in this case, the local concentration of a chemical gradient.
Morphodynamic mechanisms do not require a precise interpretation of signal concentrations or a temporal genetic program for every cell. Instead complex patterns arise through the collective spatiotemporal co-ordination of cell behaviors in the course of simultaneous cell signaling and form changes. Cells cannot be said to follow a program, but are rather moved along a developmental trajectory by continual interaction with a changing molecular-geometric microenvironment. At each moment the cell computes the behavioral changes it will undergo based on the network of transcriptional factors and signal transduction molecules it expresses and signals it receives. The cell's responses at any moment may be relatively simple (although in the long run they may have complex consequences). In morphodynamic mechanisms it is not only what happens inside responding cells that is significant. The `intermediate phenotype' at each moment is also causally determinative: that is, the shapes of, and relative distances and orientations among inducing and induced territories. Thus when an inductive interaction takes place between two territories it is not only important to know how this signal is interpreted by the receptive cells but also what are the forms of the inductive and receiving territories, and how are they changing in three-dimensional space as a result of the action of the morphogenetic mechanisms. Several experimental examples illustrate these points.
Developmental evidence
Brain development
The developing vertebrate brain is subdivided into territories expressing
specific adhesion molecules and transcriptional factors
(Rubenstein et al., 1998).
Specific signaling molecules expressed in the territory boundaries are
involved in patterning the brain. Pax6 is a transcription factor known to
affect the expression of adhesion molecules and in the mouse brain, during
stages E9.0-E12.5 (Stoykova et al.,
2000
), this protein is expressed at territory boundaries where the
neuroepithelium is folding (Grindley et
al., 1997
). Pax6 mutants exhibit morphological
abnormalities originating at these stages, involving partial failure of such
folding, enlargement of the boundary between two of the prosomeric segments of
the diencephalon, and changes in the relative sizes of the prosomeres
(Grindley et al., 1997
;
Warren and Price, 1997
). This
abnormal folding both results from and changes the relative spatial position
of the territory boundaries and thus of the genes expressed in them. It is
this reciprocity between changing shape and changing patterns of gene
expression that marks this process as morphodynamic
(Grindley et al., 1997
).
The diffusible signaling molecules Shh and Wnt7b are expressed in regions
of the developing brain altered by the Pax6 mutation
(Epstein et al., 1999;
Grindley et al., 1997
;
Warren and Price, 1997
). Both
affect proliferation and Wnt7b also affects adhesion
(Brault et al., 2001
). By
virtue of the effects of Wnt7b and Shh on proliferation and adhesion, the
territories affected by these factors undergo continual alteration in form.
But in certain cases the territories affected by Shh and Wnt7b are also
territories that express the factors. The consequence is that the
Pax6 mutant exhibits nontrivial changes in the spatial patterns of
expression of signaling genes coordinated with, and inextricable from, the
morphological effect represented by misfolding. The three-dimensional context
(i.e., form) within which morphogenetic mechanisms are deployed at one stage
in the Pax6 mutant and, presumably, the normal brain, thus have a
causal role in determining patterning in later stages. Unlike developmental
outcomes of morphostatic mechanisms, which can be schematized as two-step
processes in which the establishment of a new cell pattern leads subsequently
to a new form, during brain development changes in form and pattern
reciprocally bring one another about in a morphodynamic fashion.
Mammalian tooth development
Multiple lines of evidence indicate that tooth development employs
morphodynamic mechanisms. Mammalian cheek teeth, in particular, possess
complex morphologies consisting of different arrangements and shapes of cusps.
Tooth crowns consist of overlying enamel, produced by inner enamel epithelium,
and underlying dentine, produced by dental mesenchyme. During development,
before the formation of enamel and dentine, tooth shapes are formed by unequal
growth and folding of the inner enamel epithelial-mesenchymal interface
(Butler, 1956;
Jernvall and Thesleff, 2000
).
The formation of cusps begins from their tips and is mediated by epithelial
signaling centers, the enamel knots. Cells of the enamel knots are
non-proliferative although they express signaling molecules, such as FGFs and
Shh (Jernvall and Thesleff,
2000
) that stimulate proliferation and survival of the areas
surrounding the enamel knots. The formation of enamel knots and cusps is
roughly sequential and takes place simultaneously with signaling linked to
enamel knot formation (Jernvall et al.,
1998
) and cusp growth
(Jernvall et al., 1994
;
Kettunen et al., 2000
). Thus,
the relative locations of knots are changing while they are sending
signals.
Teeth most probably develop in a morphodynamic fashion since induction and
morphogenesis take place at the same time and interdependently. Furthermore,
to date no molecular prepatterns manifesting the final tooth cusp patterns, or
unique genes or combinatorial code for individual cusps has been reported
(Jernvall and Thesleff, 2000).
These kinds of evidence would be indicative of morphostatic mechanisms and
would also suggest that individual cusps would be relatively free to vary in
size independently of one another. However, the variational properties of
cusps within a tooth show that the presence and size of later forming cusps
depend on the position and size of earlier developing cusps
(Jernvall, 2000
). This again
suggests that formation of new enamel knots and molecular signaling depend on,
and is reciprocally linked with, the preceding morphology, which is consistent
with morphodynamic mechanisms.
Reciprocity of molecular patterning and morphogenesis is also implicated in
Tabby mouse mutants by affecting the size and overall degree of
enamel knot signaling (Pispa et al.,
1999), resulting not only in smaller teeth but also in globally
altered shapes. An empirically derived morphodynamic mechanism for tooth
formation has been recently tested using mathematical modeling
(Salazar-Ciudad and Jernvall,
2002
). This morphodynamic model, while only containing essential
components of known molecular interactions and their effects on growth, was
able to predict both the course of tooth shape development and dynamics of
gene expression patterns. Furthermore, simple changes in model parameters are
able to reproduce well known evolutionary changes in tooth shapes, suggesting
that morphodynamic mechanisms may promote evolutionary versatility
(Salazar-Ciudad and Jernvall,
2002
). The intricate manner by which developing tooth shape alters
the diffusion and local concentration of molecular signals in this
morphodynamic models suggests that predicting phenotypic effects of molecular
manipulations may be very difficult without mathematical approaches and
knowledge about developing morphology.
The preceding examples should not be taken to imply that all developmental
processes employ morphodynamic mechanisms. In the developing vertebrate limb,
for example, the pattern of skeletal elements is specified by inductive
mechanisms well before the occurrence of precartilage mesenchymal condensation
(Wolpert and Hornbruch, 1990;
Dudley et al., 2002
), the
latter being the first morphological change distinguishing skeletal tissue
from adjacent nonskeletal tissue and the result of a morphogenetic mechanism
(Newman and Tomasek, 1996
).
Although inductive and morphogenetic mechanisms acting earlier and later set
the shape of the limb bud and refine the shapes of individual elements, the
developmental mechanism that generates the basic skeletal pattern from a
homogeneous distribution of mesenchymal cells is morphostatic.
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EVOLUTIONARY IMPLICATIONS |
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It is important to note that the difference between morphodynamic and morphostatic composite mechanisms relates to how basic inductive and morphogenetic mechanisms are combined (Fig. 2). Indeed, a morphodynamic and morphostatic mechanism can involve the same basic inductive and morphogenetic mechanisms and thus the same genetic information. From what we have said in the previous paragraph it follows that morphodynamic mechanisms can produce additional forms without additional genetic information.
Because morphodynamic mechanisms can use the spatial epigenetic information (i.e., the form and relative orientations of the territories sending and receiving signals) present in the emerging phenotype at each point in development to alter later development, such mechanisms exhibit dependency on the `intermediate phenotype'. This property permits developing systems that employ morphodynamic mechanisms to generate more phenotypic variation for less molecular variation than morphostatic mechanisms. In addition to the intermediate phenotype of the forming pattern, patterns in the rest of the embryo may also influence morphodynamic mechanisms. Thus morphodynamic mechanisms acting in the context of more complex phenotypes may facilitate morphological innovation. This can be exhibited ontogenetically, where a wide variety of forms (for example teeth, or convolutions of the neocortex) can be generated by the use of the same set of mechanisms in slightly different developmental contexts, or phylogenetically, where small genetic changes can lead to significant evolutionary changes.
The integrated nature of signaling and morphogenetic aspects of development
causes morphodynamic mechanisms to prescribe a more complex relationship
between genotype and phenotype. The dependency of developmental outcome on the
intermediate phenotype in such mechanisms makes it possible for small
molecular changes to give rise to relatively large phenotypic effects in some
cases and no effects in others (Figs
3,
4). While a typical
morphodynamic mechanism will not necessarily be more prolific in generating
patterns than a typical morphostatic mechanism, the range (i.e., disparity) of
different patterns potentially produced by a given morphodynamic mechanism
will usually be wider (Fig. 4).
Conversely, in many cases genetic changes would have no phenotypic effects in
morphodynamic mechanisms (Fig.
3B). One reason for this is that patterns produced by
morphodynamic mechanisms will often vary in a `discontinuous' fashion with
small genetic changes, and the intermediate patterns would not be possible
(Fig. 3) (see
Salazar-Ciudad and Jernvall,
2002). In this sense morphodynamic mechanisms are both protean and
developmentally constrained. In contrast, for morphostatic mechanisms most
genetic changes will have small phenotypic effects
(Fig. 4), and patterns
intermediate between any two distinct ones would often be found.
|
Earlier work has suggested that over the course of evolution a
developmental pattern produced by an emergent morphostatic mechanism may
persist, while the mechanism by which the pattern is generated evolves into a
hierarchical one (Newman,
1993; Salazar-Ciudad et al.,
2001a
; Salazar-Ciudad et al.,
2001b
). In an analogous fashion, progressive partial substitution
during evolution of morphodynamic mechanisms by morphostatic mechanisms
producing the same pattern can be expected. This is because, compared to
morphodynamic mechanisms morphostatic mechanisms can produce more finely-tuned
phenotypic variations. In other words, more continuous phenotypic variation
can be produced. In addition a simpler relationship between phenotype and
genotype allows them to produce such changes relatively rapidly. These two
properties are probably adaptive for patterns under strong stabilizing
selection. Such substitution of morphodynamic by morphostatic mechanisms would
likely require many generations and may, in general, not go to completion
since in many cases it may be evolutionarily adaptive to produce the same
pattern with two different mechanisms [especially if they have different
variational properties (Nowak et al.,
1997
)].
Generally, morphological innovations have been proposed to appear more
often in later development because they are less likely to disrupt global
developmental processes at those stages
(Riedl, 1978). This suggests,
in turn, that morphodynamic mechanisms would be found more often in later
development where, in addition, already existing complex intermediate
phenotypes would allow them to produce variation, and thus respond to
selective pressures more easily. Conversely, at earlier developmental stages,
which would have had more evolutionary time to change, morphostatic mechanisms
may have become superimposed on, and in some cases, substituted for,
morphodynamic mechanisms.
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ACKNOWLEDGMENTS |
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