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Systems Biology Approaches to Development beyond Bioinformatics:

Nonlinear Mechanistic Models Using Plant Systems

Article  in  BioScience · May 2016

DOI: 10.1093/biosci/biw027

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 BioScience Advance Access published April 6, 2016
Overview Articles

Systems Biology Approaches to

Development beyond Bioinformatics:
Nonlinear Mechanistic Models Using
Plant Systems
ELENA R. ÁLVAREZ-BUYLLA, JOSE DÁVILA-VELDERRAIN, AND JUAN CARLOS MARTÍNEZ-GARCÍA

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Biological systems are complex, stochastic, and nonlinear; therefore, understanding how genes map to phenotypes remains a challenge. A complex-
systems mechanistic approach, emphasizing relations over associations, is required for understanding the emergence of cell differentiation and
morphogenesis during development. An increasing number of contemporary studies that integrate biological data into dynamic, nonlinear, and
stochastic models are providing novel explanations for development. Unfortunately, the adaptation of the biological research tradition to such
quantitative and interdisciplinary approaches is not straightforward. In an attempt to contribute to this necessary transition, drawing mainly
on our own studies as examples, we present here a nontechnical overview article of how such models are helping unravel the emergence of cell
differentiation, pattern formation, and morphogenesis. The studies reviewed here suggest that we need to reevaluate how biological causal and
functional roles are interpreted.

Keywords: gene regulatory networks, genotype–phenotype map, epigenetic landscape, systems developmental biology, nonlinear stochastic modeling

A fundamental question in biology and biomedicine 

is how genes map to phenotypes. Such mapping
depends on development, which includes the processes
mechanisms, because these are highly nonlinear, stochas-
tic, and dynamic. Ultimately, systems biology pursues an
understanding of how such dynamic processes and systems-
underlying cell differentiation and morphogenesis. In an level mechanisms underlie the emergence of the described
attempt to understand the molecular basis of such mapping, patterns.
the genomic era has produced an immense amount of data We have sought an understanding of such underlying
at the DNA, RNA, protein, and metabolic levels (Flintoft systems-level dynamical processes, which imply restric-
2005, Kim and Przytycka 2013). The statistical analysis and tions emanating from mutual interactions and feedback
integration of genome-scale data has produced important mechanisms at the genetic and nongenetic levels, as well
contributions to uncovering genotype–phenotype (G–P) as across temporal and spatial scales (as further explained
associations and the regulatory modules involved in vari- below). Together, the multilevel or multiscale dynamic
ous normal and anomalous developmental processes (Brady processes include the biological mechanisms that underlie
et al. 2011, Liberman et al. 2012, Rogers et al. 2012, Li et al. cell differentiation and reprogramming. Therefore, we refer
2013). Such practices are, mainly, of a descriptive nature, to biological systems-level mechanisms as those dynamic
because they use statistical tools to recover patterns and to processes involved in the emergence of cell differentiation
quantitatively describe them, uncovering associations with and morphogenesis. In contrast to addressing the molecular
predictive power (Ellner and Guckenheimer 2011). The mechanism of the regulation of a particular gene or com-
set of associative practices follows the so-called top-down ponent, as is generally pursued in mechanistic molecular
approach of systems biology (Tomlin and Axelrod 2007). genetic approaches, we are interested in unraveling the inte-
This approach has been very illuminating, but relying on grated mechanisms and concerted action of the interacting
a strictly associative and descriptive approach may hinder molecular and physicochemical components that underlie
understanding of the underlying biological processes and development. Indeed, explaining how a particular gene is

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Overview Articles

regulated is very useful, but on its own, it does not explain previously by pioneer theoretical biologists (Kauffman 1993,
how a cell type is specified, an organ is formed, or a disease Goodwin 1994, Solé and Goodwin 2008, Waddington 1957).
is developed. Even if we study the so-called master genes,
we are not able to understand the systems-level underlying Nonlinearity in genotype to phenotype maps
mechanisms implied in its prominent role. The systems- Despite the fact that nonlinearity is intrinsic to biological
biology approach that implies the proposal of mechanistic, and biochemical systems, reasoning in biology has tra-
dynamic models to uncover G–P mapping algorithms is ditionally followed a remarkably and instrumental linear
referred to as the bottom-up approach, and it has been cause–effect paradigm for particular components. This latter
mostly applied to well-curated regulatory modules with approach does not consider explicitly the conditional role of
clear phenotypical consequences. each part on others or the direct and indirect interactions
The top-down and the bottom-up approaches comple- among components that altogether constitute the system.
ment each other and are increasing the explanatory and pre- In a cause–effect framework, which avoids the consider-
dictive power of systems biology (Bruggeman et al. 2007). A ation of interactions and feedback loops, linear schemes of
key aspect of the bottom-up mechanistic approach is that it causation are frequently invoked (see, e.g., discussions in
considers nonlinear dynamical mapping models at different Huang 2011). The latter approach, which assumes that the
levels of organization (e.g., gene interactions and circuits, behavior of a whole system can be understood on the basis
networks, cells, tissues, organs), incorporating both molecu- of the behavior of its isolated components or their added

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lar–genetic (e.g., genes, proteins, miRNAs) and nongenetic behaviors, has been qualified as “reductionist.” In agreement
(e.g., mechanical and elastic forces and fields, chemical with previous publications (Kaneko 2006, Alvarez-Buylla
concentrations and gradients) components to understand et al. 2010a, Huang 2011), we consider that a systems-level
the G–P mapping and to uncover systems-level behaviors approach that explicitly considers interactions and the non-
and traits. Such a dynamic models study cellular behavior linear stochastic nature of underlying processes is required
as the inevitable manifestation of the intrinsic nonlinear to understanding the emergence of the observed biological
and stochastic nature of underlying networks of interacting patterns. Therefore, for the purpose of this article, by reduc-
components. Such an endeavor implies uncovering the bio- tionist paradigm, we refer to an explanatory view in which
logical mechanisms of cell differentiation and morphogen- the effect of interactions among components of interest (e.g.,
esis. In summary, in our view, bottom-up systems biology molecular species) is inadvertently ignored.
is grounded in a complex systems and dynamic mechanistic
approach. Plant development: Emergent behavior from
The importance of the nonlinear, stochastic dynamic multilevel nonlinear dynamics
nature of biological systems has been previously emphasized Plants have been useful model systems for experimentally
by many theoreticians (e.g., among others, Turing 1952, grounding and validating theoretical models. Here, we
Kaufman 1969, Meinhardt 1982, Sawyer et al. 2010). More describe how dynamical models have contributed to under-
recently, dynamical models have been validated for particu- standing the emergence of cell phenotypes and morphoge-
lar biological systems by integrating mechanistic data for the netic patterns and processes as natural consequences of the
system´s components and their interactions to study their restrictions imposed by nonlinear regulatory and dynamic
concerted action and emergent structural and dynamical systems. The cases summarized here imply dynamic emer-
consequences (Mendoza and Alvarez-Buylla 1998, Çağatay gent behaviors that scale from gene regulatory networks
et al 2009, Barrio et al. 2010). In this article, we provide an (GRNs) and epigenetic landscapes (ELs) to model cell-fate
overview of contributions using such bottom-up approach attainment at the cellular level and pattern formation at the
of systems biology grounded on experimental data. We draw tissue and organ levels (figures 1 and 2).
on almost two decades of research on complex network
models applied to plant systems. We have focused on various Multistability and cell-fate dynamics: Intracellular regulatory net-
plant organs (flower, root and leaf epidermis, root stem-cell works.  A theoretical understanding of the way in which the
niche, root cellular organization and growth, and shoot api- concerted action of multiple genes, along with physico-
cal meristem transitions) and have taken advantage of the chemical constraints and environmental factors, regulate cell
valuable experimental and molecular genetic data available ­differentiation and morphogenesis is a foundational ques-
for Arabidopsis thaliana (Mendoza and Alvarez-Buylla 1998, tion in developmental biology (Turing 1952, Waddington
Espinosa-Soto et al. 2004, Alvarez-Buylla et al. 2007, 2008, 1957, Kauffman 1969, Thom 1983, Goodwin 1984, among
2010a, Benítez et al. 2007, 2008, Azpeitia et al. 2010, Azpeitia others). Experimentally, biologists have access to the expres-
and Alvarez-Buylla 2012, Azpeitia et al. 2014). sion profiles, or gene configurations, characterizing the
Our conceptual and theoretical explorations have illu- different cell types in a multicellular organism. These con-
minated the constructive role resulting from the inevi- trasting stable cellular phenotypes are manifested despite
table interplay between feedback-based interactions among an underlying invariant genomic sequence. The process of
genetic and nongenetic components and stochasticity in cellular differentiation is therefore necessarily a consequence
real biological systems—a view that has been emphasized of epigenetic regulatory mechanisms. Given this knowledge,

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 Overview Articles

In GRN models, genes or proteins

correspond to the nodes of a network,
whereas the links among them stand
for regulatory interactions (figure 3). A
dynamical model describes mathemati-
cally the mechanisms by which the vari-
ables describing a system change in time
(Ellner and Guckenheimer 2011). In the
case of a GRN dynamical model, the
activity (i.e., gene expression) of each
component in the network is chang-
ing in time. The nonlinear character
of the system resides in modeling the
change of each gene in terms of the
activity pattern of the genes regulating
it along time. The mutual dependence
of the genes in the network imposes

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constraints and restricts the future gene
activity patterns of each gene. Whether
a given gene will be expressed or not
in future time-steps depends on the
expression level of the genes regulating
it but also on the way their interactions
condition their individual effects, pro-
ducing a nonadditive, joint regulatory
effect on it. Because of such regulatory
feedback among the genes, it is no lon-
ger possible to establish a direct causal
effect for each individual regulatory
gene (see figure 4). Therefore, the “func-
tional role” of each gene can only be
defined and understood in the context
of the system in which it is immersed.
Moreover, each gene in the network is
simultaneously subject to this regulatory
process; consequently, global, nonintui-
tive, and structured behavior emerges in
Figure 1. Emergent models at different levels of organization: (a) single-cell a self-organized manner.
multistable gene regulatory network models to study cell differentiation, A first striking behavior of such com-
(b) multicellular and epigenetic landscape models with no spatiotemporal plex regulatory networks is the existence
restrictions to study the temporal pattern of cell-fate attainment, of a discrete number of genetic con-
and (c) mesoscopic morphogenetic models. figurations that are consistent with the
restrictions imposed by the GRN and
how can we explain, in system-level mechanistic terms, the that actually coincide with observed in vivo configurations.
emergent stable gene expression profiles associated with dif- Once the network presents such a configuration, the expres-
ferent cell types? Why do the observed cellular phenotypes, sion of each gene in the network does not change anymore,
at least partially related to and implemented by the molecu- but it is stably maintained in a self-organized manner.
lar profiles, constitute qualitative discrete entities? The Such stable configurations are referred to as attractors, and
nonlinear dynamical analysis of GRNs has provided insights they have the property of being robust in the face of per-
into these questions and phenomena through the concept turbations to the system’s state (see reviews and examples
of multistability, as we further explain below. This approach in Alvarez-Buylla et  al. 2007, 2010a). Qualitatively, cell
was first proposed theoretically by Kauffman (1969) and types can be characterized or be considered as the in vivo
later validated for several biological systems (Mendoza and manifestation of attractor configurations of the global GRN
Álvarez-Buylla 1998, Von Dassow et  al. 2000, Albert and coded in the genome of a multicellular organism. This has
Othmer 2003; see reviews in Álvarez-Buylla et  al. 2010a, been experimentally validated using human cells (Huang
Dávila-Velderrain et al. 2014). et al. 2005).

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Overview Articles

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Figure 2. Schematic representations of Arabidopsis thaliana plants before and after flowering. The cell-differentiation,
tissue-patterning, or other developmental processes that have been studied using multistable GRN are indicated. In the
text, the references from which each of the GRN models illustrated here were drawn are cited.

Multistability is the property of a given GRN of attaining inside: sepals, petals, stamens, and carpels (see, e.g., Alvarez-
more than one of these attractor states. In systems-biology Buylla et  al. 2010a,b). Such a conserved pattern suggested
literature, multistability is generally accepted as the for- an underlying robust mechanism that evolved before the
mal dynamic mechanism explaining cellular differentiation, origin of the flowering plant species. We aimed at discover-
reprogramming, and dedifferentiation (Kauffman 1969, ing such a robust regulatory core. To this end, we proposed
Mendoza and Alvarez-Buylla 1998, Laurent and Kellershohn a GRN model grounded on experimental data to test, for
1999). Importantly, multistable systems are necessarily non- the first time, that a multistable GRN could partition the
linear (Ellner and Guckenheimer 2011). space of possible configurations of gene expression states
in a manner consistent with that seen in the different cell
Floral organ primordial cell-fate specification.  As a first example types of the floral meristem. This model demonstrated that
of the nonlinear perspective to plant development, we have in a real biological case, cellular phenotypes could indeed
developed a cellular level model of cell-fate determination correspond to different attractors or stable configurations of
during floral-organ specification in Arabidopsis thaliana (see gene expression states (Mendoza and Alvarez-Buylla 1998).
figures 1 and 2; Mendoza and Alvarez-Buylla 1998, Espinosa- This GRN was first published on the basis of limited avail-
Soto et  al. 2004, Alvarez-Buylla et  al. 2010a, Azpeitia et  al. able experimental data; however, since then, it has been
2014). Most flowers have four types of floral organs that are updated to incorporate additional data as they become avail-
formed with a stereotypical pattern from the outside to the able (Espinosa-Soto et al. 2004, Alvarez-Buylla et al. 2010a).

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 Overview Articles

Benítez et  al. 2008). We proposed a model simulating the

emergence of epidermal cell types in a static spatially explicit
domain. In this model, the configurations at each location
were restricted by the patterns of cell–cell movement of
some of the GRN components according to experimen-
tal data, in addition to the interactions of the GRN itself.
Interestingly, even though very similar GRNs are involved in
both cell differentiation and patterning processes, cell-type
spatial patterns are contrasting in roots (stripes) and leaves
(between random and uniform; see figure 2). The model
provided a clear example of the multistable nature of the
dynamic systems underlying cell differentiation, as well as
a case in which similar GRN modules are coopted for cell
differentiation in different tissues and may yield contrasting
phenotypes in different cellular contexts within the same
organism (Benítez et  al. 2008, Álvarez-Buylla and Benítez
2011, but see examples in other systems: Chang et al. 2006,
Figure 3. A schematic representation of a gene regulatory

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Luo et  al. 2013). Furthermore, similar regulatory motifs
network model. that involve local self-activation and lateral long-distance
inhibition, such as those uncovered for the Arabidopsis
models, have been found also for epidermal-cell patterning
Overall, these studies uncovered a set of components and in animals (Sick et al. 2006). Our models for this case have
interactions (i.e., a regulatory module) that are sufficient also uncovered the role of nongenetic restrictions during cell
to recover observed patterns of gene expression in each differentiation, such as cell geometry and the relative posi-
one of the four types of primordial cells that later on form tion of one cell layer with respect to an underlying one, both
sepals, petals, stamens, and carpels (figure 2). The regulatory being crucial for biasing the spatial pattern of hair and non-
module incorporates the so-called ABC genes, which had hair cell types in the Arabidopsis thaliana root with respect
been shown to be necessary for floral-organ specification to the pattern found in leaves (see figure 2; Benítez et  al.
in Arabidopsis using single mutants and their combinations 2008). In addition, these models enabled predictions of the
(Coen and Meyerowitz 1991). These genes directly or indi- nodes that may connect the cell-differentiation regulatory
rectly interact with several other components and modules; module with gibberelic acid signaling pathways and eventu-
we uncovered one possible set of such interactions that are ally with environmental cues (Benítez et al. 2008). Therefore,
sufficient to lead to the configurations observed during the this system offers an excellent opportunity to explore the
early stages of flower development. Furthermore, theoretical constructive role of the environment in cell-pattern evolu-
analyses of this GRN have shown that it is robust to slight tion and the role of epigenetic inheritance in plasticity and
genetic perturbations, and it has also been validated for wild adaptive evolution.
type, as well as for the gain and loss of function mutations Different research groups independently uncovered and
(for details, see Alvarez-Buylla et  al. 2007, 2010b). Finally, modeled particular subnetworks or modules involved in
these GRN models have also proven to have predictive power, epidermal-cell subdifferentiation. Each one was shown to be
because some interactions that had not been uncovered or sufficient to recover hair and nonhair cell types, as well as
proposed before were predicted in the context of the GRN the contrasting spatial patterns observed in roots and leaves
and later confirmed experimentally by other research groups (Dolan 1996, Lee and Schiefelbein 2002, Schiefelbein 2003,
(for details, see Alvarez-Buylla et al. 2007, 2010b). Pesch and Hülskamp 2004). Interestingly, however, only
when all these regulatory subnetworks or motifs were inte-
Cell–cell movement of GRN components: Restrictions underlying grated in a single network were the spatial patterns robustly
spatial pattern formation.  To go from single-cell to tissue-level recovered (Benítez and Álvarez-Buylla 2010, Álvarez-Buylla
coupled patterns of cell differentiation, we have explored and Benítez 2011). These results suggest that redundant
higher-order systems in other plant organs. The molecular regulatory motifs or subnetworks might be important for the
genetic basis of cell subdifferentiation (hair and nonhair) emergence of systems-level characteristics and behaviors,
in the Arabidopsis thaliana epidermis of roots and leaves such as the robustness and resilience of biological patterns
has been extensively studied experimentally (see reviews (Álvarez-Buylla and Benítez 2011). Finally, this system also
in Hui et  al. 2013, Benítez et  al. 2014). GRN models have served to show that cell fate is not due to either internal
integrated such molecular experimental data for this cell or external factors; rather, it emerges from the feedback of
differentiation process and have been useful to uncover both. It illustrates that positional information during cell
the multistable module that regulates the cell subdifferen- differentiation emerges from the dynamic interaction of
tiation process (figure 2; Mendoza and Álvarez-Buylla 1998, intracellular and extracellular components. This argument

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Figure 4. A schematic representation of gene feedback-based regulatory interactions: (a) Gene y is regulated by two
different genes (w and x). A cause–effect view (here reductionist) would imply explaining the behavior (expression)
of gene y exclusively as the additive behavior of the genes w and x, potentially ignoring feedback-based interactions.
(b) A hypothetical feedback-based interaction: If the behavior of gene y regulates itself, its regulator (x), or both,
a nonlinear view would be necessary in order to interpret and model it, given that in such scenario, the effect
(behavior of y) becomes part of the cause.

is further elaborated below, using other examples at higher Further simulation studies were performed to postulate
levels of organization. novel missing interactions (Azpeitia et al. 2013). Some of the
interactions were later corroborated by independent experi-
Root stem-cell differentiation and spatial patterning. Stem-cell mental studies (Azpeitia et al. 2013), once again document-
niches (SCN) are fundamental for multicellularity; they ing the predictive power of GRN models. In this case, the
include proliferation and differentiation capabilities at the spatial arrangement of each gene-expression configuration
same time and in restricted spatial domains. These cel- associated with each type of stem cell was also recovered
lular structures have generic traits of cellular organization by incorporating the patterns of intercellular movements
conserved in plants and animals, suggesting underlying bio- for some of the SCN–GRN components (Azpeitia et  al.
generic mechanisms (Sablowski 2004, Azpeitia and Álvarez- 2011). Interestingly, the network of networks that followed
Buylla 2012). Conserved patterns include the position of the the intracellular configuration for each cell at each spatial
organizer cells at the center of the SCN that have very low location (40 nodes) converged to a single robust attractor
rates of proliferation. These cells are surrounded by stem that mimicked the spatial arrangement of different gene-
cells with slightly higher proliferation rates that first transit expression configurations observed in the actual Arabidopsis
to a domain of active proliferation, then to one of elonga- root SCN. Ongoing research is explicitly incorporating into
tion, and later on to one of differentiation. Plant SCNs are this model hormone signaling, cell proliferation, and other
more amenable to in vivo experimental studies than those components to understand how SCN size is established and
on animals. Therefore, they may be useful for uncovering spatiotemporally maintained during development.
such biogeneric mechanisms. We have used the root SCN The results of all these models for single cells and static
for integrating a dynamic GRN model based on available spatial domains have been useful to support the hypothesis
data. We used the model to test the sufficiency of uncovered that cell types emerge naturally as self-organized properties
pathways and then proposed a regulatory module able to of the underlying molecular regulatory network, as well as
recover the gene-expression configurations characteristic additional restrictions that couple GRN dynamics, such as
of the four precursor stem cell types or initial cells: vascu- cell–cell movement of some of the networks components or
lar initials, cortex–endodermis initials, quiescent center, cell geometry (figures 1 and 2).
and columella—that is, epidermis-lateral root cap initials The detailed analysis of the proposed models through
(figure 2; for details, see Azpeitia et  al. 2010). This study virtual mutation experiments provides insights into the
showed that the two pathways that had been thought to be impact on pattern formation that the different genes within
both necessary and sufficient to recover the cell types and the GRN can have. Importantly, it demonstrates that such
their spatial patterns within the root SCN are not sufficient. effects depend on the whole regulatory system rather than

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 Overview Articles

on individual genes or molecular components. Certain genes influence, a noise effect that varies randomly each time.
reach the master title when their strong effect on the phe- Introducing stochasticity into nonlinear dynamical models
notype is described experimentally in developmental func- has provided interesting results, suggesting, for example,
tional genetic studies (see, e.g., Williams and Fletcher 2005). that noise may play a constructive role in biology and that
Dynamical GRN models enable a system-level mechanistic present-day biological networks might have evolved in noisy
interpretation to their apparent “more relevant” role in conditions (Álvarez-Buylla et al. 2008, Tawfik 2010). In order
development—relative to the other genes without the title— to explore this possibility in a plant developmental process,
when their altered expression causes the GRN to attain we studied the role of stochastic perturbations on the GRN
altered stable configurations or attractors. An important underlying floral-organ primordial cell fates. We addressed
contribution of nonlinearity in this respect is the realization, whether such stochastic GRN recovered, in addition to the
through dynamical modeling, of the fact that the quality that observed cell states, the robust temporal morphogenetic pat-
gives their higher rank to master genes is indeed a systemic tern with which such states are attained during early flower
property emerging from the joint effect of the gene in ques- development (Álvarez-Buylla et al. 2008).
tion and its interacting partners and not from itself: Out of In flowering plants, a floral meristem is sequentially
justice to the collaborating genes, perhaps the master title partitioned into four regions from which the floral-organ
should refer to a core regulatory module rather than to a primordia are formed and sequentially give rise to sepals in
gene alone. For example, in the floral-organ specification the outermost whorl; petals in the second; stamens in the

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GRN model (Mendoza and Alvarez-Buylla 1998, Espinosa third; and, almost concomitantly, carpels in the fourth, in
et al. 2004, Álvarez-Buylla et al. 2010a), a mechanistic expla- the central part of the flower. This spatiotemporal pattern-
nation for the important role of the ABC master homeotic ing is widely conserved among angiosperms. By introducing
genes was provided. Their interactions with several other stochasticity (noise) into the GRN of organ identity genes,
genes in the context of a dynamic GRN model guarantee the most probable temporal order in which the uncovered
that their loss of function mutations yield altered attractors attractors are attained in the simulated stochastic model is,
that qualitatively correspond to those associated with the in fact, consistent with the temporal sequence in which the
homeotic organs observed in the mutant flowers. specifications of corresponding primordial cell types are
observed in vivo. The model provided, then, a novel expla-
Populations of cells: Stochastic exploration of nation for the emergence and robustness of the ubiquitous
epigenetic landscapes and developmental dynamics temporal pattern of floral-organ primordial cell specifica-
In addition to nonlinearity, a property that is very relevant tion. In addition, it also allowed predictions on the popula-
for the study of biomolecular processes and development is tion dynamics of cells with different genetic configurations
stochasticity (Tawfik 2010). What happens if we consider in during development (for details, see Alvarez-Buylla et  al.
our simple mechanistic models of development a more real- 2008, Azpeitia et al. 2014). This model enables the analysis
istic approximation to the inner workings of biomolecular of cell-state transition events in the establishment of multi-
systems by including both nonlinearity and stochasticity? cellular hierarchies. Therefore, it constitutes a new approach
A quite interesting problem in developmental biology is to understanding a morphogenic process by uncovering
the following: If molecular regulatory events at the ­cellular restrictions that the GRN interactions impose also on the
level are intrinsically stochastic, how is it possible that transitions among the attractors or cell fates and not only on
we observe a phenomenological, robust, and seemingly the number and types of the stable states themselves.
deterministic process during development? (Zernicka-Goetz The stochastic GRN model of floral-organ specification is
and Huang 2010, Oates 2011). Models of plant develop- equivalent to a stochastic exploration of what Waddington
ment again have given interesting insights into this issue called the “epigenetic landscape” (EL; figures 1 and 5). Such
(figures 1 and 3; Alvarez-Buylla et al. 2008, Villarreal et al. a landscape emerges from the GRN, and it can be character-
2012, Azpeitia et al. 2014). ized mathematically (Villareal et al. 2012). Several different
The GRN models briefly described in the previous section approaches to formalize and to numerically analyze the EL
are deterministic. This means that for each gene in the net- have recently been proposed and are reviewed elsewhere
work, we only need to specify which genes are regulating it (Wang et al. 2010, 2011, Zhou et al. 2012, Davila-Velderrain
and the functional form of their joint regulation in order to et  al. 2015a). Nonetheless, given the multidimensional and
know exactly the effect on its expression rate of change given nonlinear nature of such epigenetic landscapes, in most
the current state of each gene in the network. Such models cases, a numerical exploration such as that proposed in
are useful tools, as was shown above. But in order to explain Alvarez-Buylla and colleagues (2008) is required (see also
the patterns of transitions among cell states or attractors figure 5). More recently, an approach to study the reconfigu-
during actual developmental processes, further modeling ration of the EL that emerges as a result of quantitative alter-
considerations may be required. Stochastic GRN models are ations of the decay rates of particular GRN components was
becoming useful as such means. proposed (Davila-Velderrain et  al. 2015b). This study pro-
In a stochastic GRN model, the joint regulatory effect dis- vides further explanations and predictions concerning the
cussed in the previous section also depends on a stochastic phenotypical impact of quantitative alterations of particular

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Figure 5. A schematic representation of the epigenetic landscape associated with the GRN for flower development and
uncovered by a stochastic exploration. Cell gene-expression configurations corresponding to the attractors are represented
in the bottom of each basin (in this case, associated with the cell states characteristic of four inflorescence cell types and
four floral organ primordial cell types: sepals, petals, stamens, and carpels). Noise (randomness represented by dice)
or stochastic modeling is used in order to uncover the structure of the landscape, the latter being manifested by the
differential likelihood of cell-state transitions (here represented with arrows).

nodes. Such alterations can result from perturbations in sig- ethylene in the root (figure 2) and can now be integrated
nal transduction pathways or to the physicochemical fields with GRN models and EL reconfiguration analyses.
connected to the GRN under analysis. Models to study how An additional application of EL formalisms to under-
such signaling pathways process information and filter noise standing Arabidopsis developmental mechanisms concerns
(Díaz and Álvarez-Buylla 2009) have been proposed for the GRN that underlies the transition from vegetative

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 Overview Articles

(VM) to inflorescence meristem (IM) and then into flower frameworks that consider various levels of organization and
meristems (FM) at the shoot apical meristem (SAM; morphogenetic patterning.
figure 2; Pérez -Ruiz et al. 2015). In this study, experiments Key to these multilevel models is to postulate processes
on the role of a MADS-box gene, AGAMOUS LIKE14 that generate the cells’ positional information at all times
(AGL12)/XANTAAL2(XAL2), yielded apparently contra- and which produce changes in the operation of the invari-
dictory data. The overexpression lines of this gene pro- ant underlying GRN accordingly. Such models can be used
duced early flowering and at the same time caused a loss to address issues concerning the regulation of the size and
of determinacy in flowers, especially under short days. We dimension of tissues, as well as the relative position of organs
put forward a multistable GRN module that incorporates a (Alvarez-Buylla et al. 2007, Swat et al. 2015). Concordantly,
set of XAL2 interactions able to recover the observed gene we have started to put forward dynamic spatiotemporal
expression profiles in different SAM stages for the main models that consider GRNs in cellularized domains and that
regulators discovered up to now to be involved in such encompass the aforementioned sources of extrinsic con-
developmental processes. We used this model to reconcile straint from fields of mechanic-elastic forces or hormones
and to provide an explanation for the two apparently con- (Alvarez-Buylla et al. 2007, Barrio et al. 2010, 2013).
tradictory phenotypes of the 35S::XAL2 lines. An EL model In addition to understanding how mechanics, geometry,
for the proposed XAL2 GRN module showed that overex- and growth contribute to the formation of functional and
pression of this gene, in the context of the GRN module robust structures (Mirabet et  al. 2011), we must consider

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proposed, yielded a novel attractor that combined IM and that these sources of additional constraints not only influ-
FM characteristic genes (figure 2). Such a combined attrac- ence each other but are also coupled with at least two other
tor is reminiscent of the mixed behavior (determinate and fundamental dynamics coming from regulatory networks
indeterminate) of the flower cells observed in overexpres- and cell proliferation. In addition, these dynamical processes
sion lines. Furthermore, our EL analyses suggested that occur at different temporal and spatial scales. For example,
transitions from FM to this attractor could explain the loss chemical signals that are produced or excreted from cells
of determinacy observed in the 35S::XAL2 lines and, at the to the extracellular matrix arrange themselves in space and
same time, accelerate the transition from VM to IM and time to form macroscopic patterns, which, in turn, affect
then to FM (figure 2). This model provides a clear hypoth- GRNs in each cell, thereby biasing its dynamics toward dif-
esis for the dynamic developmental mechanism that may ferent gene-expression configurations. In other words, in
underlie the phenotypes of this MADS overexpression and order to accomplish the extraordinary choreography implied
of several others. The model suggests that in this and likely by morphogenesis (without a choreographer!), the behavior
other cases, we are not faced with a reprogramming of of the chemicals or mechanic-elastic forces and communi-
floral to inflorescence cells but rather with the emergence cation mechanisms should be coupled with the dynamics
of a new cell type with mixed identities and behaviors, as of the GRN in such a way that the positional cues bias the
well as an increased probability of transiting into it. This attractor of the GRN, and, at the same time, the modified
application illustrates that EL models and analyses can be gene activity configuration of the GRN regulates the spatial
used as well to further understand the dynamic mecha- pattern of chemical concentrations (Álvarez-Buylla et  al.
nisms underlying cell reprogramming and dedifferentia- 2007). We refer to the models that capture such dynamics
tion in plants and animals. as models of cooperative nonlinear dynamics (Barrio et  al.
2013).
Spatiotemporal cellular patterns in plant tissues: The general problem of cooperative nonlinear dynam-
Feedback of GRNs and extracellular sources of ics could be stated as follows: The GRN in each cell in
constraint the meristem is in a state of undifferentiated complacency
The GRN models reviewed above only consider a single- but may be producing certain transcripts and signals that
cell developmental process, able to recover different gene regulate other genes. The signals and molecules inside the
expression profiles; a GRN coupled with cell–cell movement cell, or in the intercellular space, may be altered via certain
of some of its components in static spatial domains, able to signal transduction pathways that respond to some physi-
attain arrangements of gene-expression configurations that cochemical field that alters their regulation and molecular
mimic actual cellular patterns in plant tissues; or popula- concentrations in different regions of space. Thus, a geo-
tions of cells, able to recover temporal patterns of transition metrical pattern is formed in space, which, in turn, provides
among cell states by updating their states independently each genetic network with a chemical environment that also
of each other (see figures 1 and 5). During multicellular depends on such spatial pattern. We developed a multilevel
developmental processes, in vivo groups or populations of model of cooperative dynamics for the case of the GRN
cells attain distinct fates with certain spatial and temporal implied in floral-organ specification. The model suggested
dynamics that occur concomitantly. Such spatiotemporal that a dynamically changing extracellular heterogeneous
dynamics and patterns emerge from dynamic feedback chemical concentration may be underlying the accom-
interactions with physicochemical fields and cell prolif- modation of the ABC genes in the observed spatial pattern
eration dynamics. Such processes imply multilevel modeling (Álvarez-Buylla et al. 2007, Barrio et al. 2010).

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Overview Articles

Mechanical forces provide cues for heterogeneous cellular Given the nongenetic character of developmental dynam-
behaviors by establishing sources of positional informa- ics, phenotypic variation to a great extent has been neglected
tion, thereby contributing to the regulation of morphogen- in the study of evolution. A deviation from a linear causation
esis (Wolpert 1969, Meinhardt 1982, Alvarez-Buylla et  al. view of development would potentially affect the rate and
2007, Barrio et  al. 2008, Hamant et  al. 2010, Barrio et  al. direction of evolution, however (see, e.g., Alvarez-Buylla
2013). Recent work has started to uncover the molecular et  al. 2007b, Jaeger et  al. 2012). Empirical evidence of
mechanisms by which mechanic-elastic forces are sensed by the evolutionary relevance of network structure and gene
intracellular GRNs (Ning et al. 2009), as well as the role of interaction—and therefore nonlinearity—on evolutionary
myosin, actin, and tubulin fibers in cell structuring and in dynamics at the molecular level is starting to emerge (Balleza
the transduction of changes in mechanical and elastic forces et al. 2008). Evolutionary forces, functional constraints, and
into GRN signals (Hamant et al. 2010, Mammoto et al. 2012, molecular interactions are conditionally dependent on the
Romero et al. 2015). systems level and ensure that small changes within the
GRN can yield large phenotypical alterations (Kauffman
Organogenesis: The cooperative dynamics of 1993, Purugganan 2004, Álvarez-Buylla et al. 2010a, Davila-
physicochemical fields and cell proliferation Velderrain et  al. 2014 and references therein). In addition,
in the root the origin of novel core GRNs may underly the emergence
In line with our view on cooperative dynamics, we devel- of evolutionary innovations (Wagner 2015).

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oped a two-dimensional simulation model that integrates Following the above line of thought, in a recent study,
the dynamics of physical and chemical fields coupled with we tested whether there is evidence supporting the idea
cell proliferation dynamics, using Arabidopsis root as a study that functional constraints associated with a GRN mod-
system of a SCN (figures 1 and 2; Barrio et  al. 2013). In ule underlying the dynamics of a developmental process
order to test our theoretical propositions, we quantified the could play a strong role in constraining evolutionary rates
characteristic cellular patterns in the root. Our model was at the molecular level (Davila-Velderrain et  al. 2014). We
able to reproduce cellular patterns (size and proliferation argue that the study of the molecular evolution of the genes
rates) observed in real roots. It provides a proof of principle involved in regulatory networks that have been uncovered
that coupled physical fields and chemical processes, under with dynamical GRN models could help uncover general
active cell proliferation, give rise to patterns observed in evolutionary principles, given that such models allow a rig-
multicellular organs and SCNs (Barrio et al. 2013, Romero orous distinction between structure and function (genotype
et al. 2015). This mechanism of cooperation provides a gen- and phenotype). We used as case of study the GRN of flower
eral model for one possible way in which the dynamics of development described above. We reasoned that the func-
physicochemical fields and active cell proliferation give rise tional constraint associated with a core regulatory module
to positional information (Barrio et al. 2013). The proposed could also play a strong role in constraining evolutionary
framework may be extended and modified to model other rates at the molecular level, and recently, we showed evi-
SCNs and also to propose GRNs coupled with the three dence suggesting that this is the case (for details, see Davila-
types of dynamics incorporated in the root SCN model. Velderrain et  al. 2014). Overall, the empirical evidence of
Other multilevel modeling platforms and approaches have the evolutionary relevance of network structure on gene
been recently put forward (Boudon et al. 2015). evolutionary patterns is in agreement with our argument for
the nonindividual role of master genes mentioned above and
Evolutionary implications of complex G–P feedback for the relevance of the nonlinear character of the regulatory
mapping: Eco–evo–devo and the constructive role systems in which they participate.
of the environment Furthermore, biological networks of both uni- and mul-
Historically, population-level models in evolution have ticellular organisms seem to have evolved to be able to cope
been developed under certain simplifying assumptions. with environmental impacts (i.e., to be robust) and, at the
Two salient assumptions are (1) the idea of genetic change same time, to change and adapt to new conditions (i.e., to
as a direct indicator of phenotypic variation and (2) the be plastic), a qualitative property consistent with what is
additivity of genetic effects on the phenotype (Wilkins AS. referred to as criticality in nonlinear dynamics (Shmulevich
2008). A more faithful model of biological evolution should et al. 2005, Balleza et al. 2008). Available studies suggest that
explicitly consider a G–P map and back, a developmental critical dynamics is a generic characteristic of biological
mechanism which specifies how phenotypic variation is gen- networks, which seems to imply evolutionary advantages
erated (Alberch 1991) in an analogous way to that in which for living organisms that are required to be robust and
positional information emerges as a result of the feedback adaptable at the same time (Balleza et al. 2008). This trait of
between internal and external restrictions (Wolpert 1969, underlying epigenetic mechanisms of development implies
Álvarez-Buylla et al. 2011). A nonlinear perspective is man- important constraints to the evolutionary patterns of phe-
datory to understand how phenotypic variation is generated notypic variation (i.e., the resulting balance between phe-
given a genetic background—or, in other words, to study notypic conservation and diversity) and, at the same time,
the dynamic system-level mechanistic basis of the G–P map. postulates a dynamic mechanism for the large phenotypical

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 Overview Articles

impacts of small genetic alterations (see Alvarez-Buylla et al. chemical and physical extrinsic conditions are the focus
2010a). The question of how such critical networks evolved of ongoing research. The possibility of actually accounting
is under active investigation in several research groups (see, experimentally for these physical processes—in an attempt
e.g., Torres-Sosa et al. 2012). It is important to note that the to understand how cellular decisions occur during tissue
dynamical analysis of network models is particularly help- patterning—will go beyond cell culture studies. Multilevel
ful to uncovering the evolutionary relevance of nonlinear approaches, grounded in experimental data, will yield more
regulatory systems. Network dynamics approximate phe- accurate models of morphogenesis during normal devel-
notypical, functional behaviors not directly accessible for opment and also under altered conditions, such as those
the structural properties of gene sequences or static wiring experienced in cancerous growths in humans. Plant systems
diagrams alone. The examples above show how dynamics are promising experimental models to propose and test such
and conventional molecular evolutionary analyses can be models and will continue to illuminate the biogeneric mech-
integrated. anisms at play during both plant and animal development.
Finally, we postulate that the consideration of complex The merging of conceptually clear theories, computa-
networks that incorporate both intracellular, genetic, and tional-mathematical tools, and molecular–genomic data
external components as well as models of cooperative into coherent frameworks is at the basis of a much-needed
physicochemical, cell proliferation, and regulatory dynam- nonlinear, dynamic, system-level explanatory and predic-
ics (Barrio et  al. 2013) may also contribute to understand- tive approach to development and to evolution. Once again,

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ing the constructive role of the environment in phenotypic plants are becoming critical systems for such an integrated
evolution. As we summarized here, phenotypical evolution and broad comparative approach.
and development cannot be understood from a linear com-
bination of the action of genes. In addition to understanding Acknowledgments
the mapping of genotypes to phenotypes, a major challenge ERAB’s work was supported by Consejo Nacional de
in the postgenomic era therefore consists of understanding Ciencia y Tecnología (CONACYT), Mexico (grant nos.
how inheritance emerges as a consequential process result- 240180, 180380, and 152649), and by Universidad Nacional
ing from the interplay between developmental processes and Autónoma de México–Dirección General Asuntos del
environmental dynamics. Personal Académico– Programa de Apoyo a Proyectos de
Investigación e Innovación Tecnológica (UNAM–DGAPA–
Conclusions PAPIIT grant nos. 203214, IN203814, and IN211516). We
Even though genetic-based approaches have been favored, it appreciate the help of Diana Romo in various tasks. We
is recently being accepted that the richness and robustness thank Estephania Sluhan for drawing figure 2. We thank
of biological forms are not encoded in the genes but rather the editor and three anonymous reviewers for their com-
emerge from their interactions and nongenetic components. ments, which greatly helped improve the text. ERAB and
Recent research is consistently showing that the physical JDV acknowledge the Centro de Ciencias de la Complejidad
forces and constraints imposed by biological structures are (C3) at UNAM.
fundamental for understanding development, in agreement
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of genotype to phenotype mapping: derivation of epigenetic landscapes systems and in uncovering patterns supporting this perspective through the
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256: 75–81. projects involving the interaction between art and science.

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