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Development

miR-9 and timing of neurogenesis (Coolen 2012)

Summary: 

This Boolean model displays the subtle role of miR-9 in the course of neural specification in zebrafish.

Figure 1: Green arrows represent positive regulations, whereas red T arrows represent inhibitory interactions. Dotted lines represent suspected (but not yet molecularly characterized) direct or indirect interactions, which prevent the expression of a gene in the progenitor or neuronal precursor states, such as elavl3/HuC inhibition in progenitors.

The node P denotes a proliferating progenitor state (P=1, N=0). It is defined by the expression of Her6 and/or Zic5. The node N denotes the commitment of a progenitor into a neural precursor (P=0, N=1).
By inhibiting genes with opposite effect on neural differentiation, miR-9 activity generates an ambivalent state (P=0, N=0) poised for responding to both progenitor maintenance and commitment cues.

Model simulations qualitatively recapitulate all the experimental results presented in Coolen et al (submitted), for the wild-type as well as for various mutant situations (including loss-of-functions, ectopic gene expressions, and miR-9 target protection by morpholinos).

Curation
Submitter: 
Chaouiya (Thieffry)

Drosophila mesoderm specification

Summary: 

This logical model encompasses 48 components and 82 regulatory interactions controlling mesoderm specification during Drosophila development, thereby integrating all major genetic processes underlying the formation of four mesodermal tissues. The model is based on in vivo genetic data, partly confirmed by functional genomic data.

Model simulations qualitatively recapitulate the expression of the main lineage markers of each mesodermal derivative, from developmental stage 8 to 10, for the wild type case, as well as for over twenty reported mutant genotypes.

This model has been used to systematically predict the effects of over 300 loss- and gain-off unction mutations, and combinations thereof. By generating specific mutant combinations, several novel predictions experimentally could be validated, demonstrating the robustness of model.

Curation
Submitter: 
Denis Thieffry

Primary sex determination of placental mammals

Summary: 

Background
Primary sex determination in placental mammals is a very well studied developmental process. Here, we aim to investigate the currently established scenario and to assess its adequacy to fully recover the observed phenotypes, in the wild type and perturbed situations. Computational modelling allows clarifying network dynamics, elucidating crucial temporal constrains as well as interplay between core regulatory modules.
Results
Relying on a comprehensive revision of the literature, we define a logical model that integrates the current knowledge of the regulatory network controlling this developmental process. Our analysis indicates the necessity for some genes to operate at distinct functional thresholds and for specific developmental conditions to ensure the reproducibility of the sexual pathways followed by bi-potential gonads developing into either testes or ovaries. Our model thus allows studying the dynamics of wild type and mutant XX and XY gonads. Furthermore, the model analysis reveals that the gonad sexual fate results from the operation of two sub-networks associated respectively with an initiation and a maintenance phases. At the core of the process is the resolution of two connected feedback loops: the mutual inhibition of Sox9 and ß-catenin at the initiation phase, which in turn affects the mutual inhibition between Dmrt1 and Foxl2, at the maintenance phase. Three developmental signals related to the temporal activity of those sub-networks are required: a signal that determines Sry activation, marking the beginning of the initiation phase, and two further signals that define the transition from the initiation to the maintenance phases, by inhibiting the Wnt4 signalling pathway on the one hand, and by activating Foxl2 on the other hand.
Conclusions
Our model reproduces a wide range of experimental data reported for the development of wild type and mutant gonads. It also provides a formal support to crucial aspects of the gonad sexual development and predicts gonadal phenotypes for mutations not tested yet.

Curation
Submitter: 
C. Chaouiya

Drosophila eggshell patterning

Summary: 

The Drosophila eggshell constitutes a remarkable system for the study of epithelial patterning, both experimentally and through computational modeling. Dorsal eggshell appendages arise from specific regions in the anterior follicular epithelium that covers the oocyte: two groups of cells expressing broad (roof cells) bordered by rhomboid expressing cells (floor cells). Despite the large number of genes known to participate in defining these domains and the important modeling efforts put into this developmental system, key patterning events still lack a proper mechanistic understanding and/or genetic basis, and the literature appears to conflict on some crucial points.
We tackle these issues with an original, discrete framework that considers single-cell models that are integrated to construct epithelial models. We first build a phenomenological model that reproduces wild type follicular epithelial patterns, confirming EGF and BMP signaling input as sufficient to establish the major features of this patterning system within the anterior domain. Importantly, this simple model predicts an instructive juxtacrine signal linking the roof and floor domains. To explore this prediction, we define a mechanistic model that integrates the combined effects of cellular genetic networks, cell communication and network adjustment through developmental events. Moreover, we focus on the anterior competence region, and postulate that early BMP signaling participates with early EGF signaling in its specification. This model accurately simulates wild type pattern formation and is able to reproduce, with unprecedented level of precision and completeness, various published gain-of-function and loss-of-function experiments, including perturbations of the BMP pathway previously seen as conflicting results. The result is a coherent model built upon rules that may be generalized to other epithelia and developmental systems.

Here, we provide the two single cell models (phenomenological and mechanistic).

The Python prototype to simulate epithelial models together with all model files are given on a different page.

The multicellular model versions are also available at the EpiLog model repository.

Curation
Submitter: 
C. Chaouiya

Drosophila Dpp Signalling pathway

Summary: 

Drosophila DPP (TGF-beta homolog) signalling pathway is triggered by ligand-induced formation of heterotetrameric complexes consisting of two type II receptors and two type I receptors with intrinsic serine/threonine kinase activity. The type I receptor (SAX or TKV) is phosphorylated by the constitutively active type II receptor kinase (Punt). Consequently, the complex becomes active and phosphorylates the receptor-regulated Smads (R-Smads). Phosphorylated R-Smads (MAD and Smox) form complexes with a common-mediator Smad (Medea) and translocate into the nucleus, where they regulate the transcription of target genes in co-operation with other transcription factors (nejire, schnurri). DPP is a morphogen, i.e. a molecule distributed in a concentration gradient that elicits different cell fates as a function of its concentration, thereby organizing a series of cell types in a defined spatial array. In response to DPP gradient, cells adopt different fates. The establishment of dpp gradient involves the proteins SOG and TSG. These proteins together capture the DPP ligand and prevent its binding to the receptor (Punt). The heteromeric complex (SOG, DPP, TSG) then release the DPP ligand, a process involving the cleavage of SOG by Tolloid (a metalloprotease). Other TGF-beta signals, Glass-bottom-boa (GBB) and Screw (SCW), help DPP to potentiate cells to respond. SCW and GBB are never expressed together in the same region and affect different cells during: i) early D/V patterning of the embryo and specification/differentiation of dorsal cells (if there is no screw, dpp alone is unable to establish the D/V pattern and embryo lack amnioserosa); ii) the development of adult structures such as the wing. GBB or SCW form heterodimeric complexes with DPP. These heterodimers can only signal through TKV, while SCW/SCW and GBB/GBB signals trough SAX, and DPP/DPP trough TKV and SAX. To model DPP signalling and the formation of the gradient, we have considered three different levels for the TKV receptor (0, 1, 2) and the MADMED effector (0, 1, 2). The regulatory graph also accounts for the potentiation of responding cells due to association of DPP and SCW, or of DPP and GBB. Activated by MADMED, DAD is a pathway inhibitor that can modulate the pathway activity from high to low signalling. DAD works by abrogating the phosphorylation of the MADMED complex by TKV or SAX, thus involving a negative circuit between DAD and the MADMED complex. In addition, BRK another inhibitor of the DPP pathway can block the transcription of dad. Our model reproduces the formation of the DPP signalling gradient and accounts for the role of the heterodimers signalling in cell potentiation. To simulate DPP signalling, we start from an initial state corresponding to non differentiated cell, that can receives high or low level of DPP signal. The use of ternary nodes enables us to account for differential effects of different DPP levels (gradient). The cells receiving high level expression display the hetero-dimers SCW/DPP or GBB/DPP and correspond to Tld expression area, which promotes DPP gradient formation. In presence of medium DPP, TSG and SOG but no TLD are initially needed to capture homo- or hetero-dimer, diminishing pathway signalling intensity (expression level 1 for TKV and MADMED). In presence of high pathway signalling, two situations occur: i) in cells potentiated by SCW: a sequestering complex (SOG/TSG/ DPP/SCW) will release the signalling molecule upon TLD clivage, in addition to normal DPP signalling. This leads to a higher signal transduction. ii) in cells potentiated by GBB, the situation is similar but involve a different heterodimer (GBB/DPP). These situations correspond to two different stable states with high TKV and MADMED (level 2), denoting that more receptors are required to enable a higher level of nuclear MADMED. We consider five different initial states: i) the first one corresponds to the absence of signalling, i.e. absence of DPP; ii) the second one corresponds to medium signalling, characterized by the presence of Dpp at level 1 and of SCW; iii) the third one corresponds to medium signalling, characterized by the presence of Dpp at level 1 and of GBB); iv) the fourth one corresponds to the presence of DPP at level 2 and of SCW; v) the last one corresponds to the presence of DPP at level 2 and of GBB. These set of initial states enable the simulation of five situations. No signalling, two medium and two high signalling that characterize the behavior of the pathway. The stable state obtained with the no signalling simulation shows the absence of binding of the ligands to the receptors TKV and Punt (level of expression 0) and the non activation of target nodes. These medium signals simulations in presence of DPP, show the activation of the receptors (level of expression 1) and subsequent signalling cascade leading to the activation of pathway's targets. These medium signal are defined by the level of expression 1 for DPP, MADMED and TKV while in the high signalling sets, these nodes are expressed at level 2. The node Tkv is multi-valued because the high signalling is characterized by the binding of hetero dimers (DPP/SCW or DPP/GBB) signalling through TKV. Note that GBB and SCW don't have the same expression pattern. For more details on Dpp signalling pathway regulation see [1]; [2]; [3]; [4]; [5].


References

Curation
Submitter: 
Abibatou MBODJ & Denis THIEFFRY

Gap Model

Summary: 

This manuscript focuses on the formal analysis of the gap-gene network involved in Drosophila segmentation. The gap genes are expressed in defined domains along the anterior–posterior axis of the embryo, as a response to asymmetric maternal information in the oocyte. Though many of the individual interactions among maternal and gap genes are reasonably well understood, we still lack a thorough understanding of the dynamic behavior of the system as a whole. Based on a generalized logical formalization, the present analysis leads to the delineation of: (1) the minimal number of distinct, qualitative, functional levels associated with each of the key regulatory factors (the three maternal Bcd, Hb and Cad products, and the four gap Gt, Hb, Kr and Kni products); (2) the most crucial interactions and regulatory circuits of the earliest stages of the segmentation process; (3) the ordering of different regulatory interactions governed by each of these products according to corresponding concentration scales; and (4) the role of gap-gene cross-interactions in the transformation of graded maternal information into discrete gap-gene expression domains. The proposed model allows not only the qualitative reproduction of the patterns of gene expression characterized experimentally, but also the simulation and prediction of single and multiple mutant phenotypes.

Curation
Submitter: 
C. Chaouiya

The Anterior-Posterior Boundary (Gonzalez et al. 2008)

Summary: 

The Hedgehog (Hh) signalling pathway plays a crucial role in animal embryonic and organ development. In the wing imaginal disc of Drosophila melanogaster, Hh is induced and diffuses from the posterior compartment to activate the corresponding pathway in cells immediately anterior to the boundary. In these boundary cells, the Hh gradient induces target genes in distinct domains as a function of the Hh concentration. One Hh target is its own receptor Patched (Ptc), which sequesters Hh and impedes further diffusion, thereby refining the boundary.

We have delineated a multivalued logical model of the patterning process defining the cellular anterior-posterior boundary that includes the formation of Hh gradient and Hh signalling transduction. This model accounts for the activation of Hh target genes mediated by positive (CiA) and negative (CiR) regulatory products of the gene cubitus interruptus (ci). Wild-type and mutant simulations are carried out to assess the coherence of the model with experimental data and to obtain biological insights into this fundamental process.

In addition to recapitulating experimental data, our logical analysis leads to the delineation of three crucial features. First, CiA should be present in all boundary cells. Second, Ptc is regulated by CiA, but also tentatively by CiR. Third, the model predicts that Engrailed acts at different functional levels in boundary and posterior cells.

Curation
Submitter: 
C. Chaouiya

DV boundary formation of the Wing imaginal disc (Gonzalez et al. 2006)

Summary: 

The larval development of the Drosophila melanogaster wings is organized by the protein Wingless, which is secreted by cells adjacent to the dorsal–ventral (DV) boundary. Two signaling processes acting between the second and early third instars and between the mid- and late third instar control the expression of Wingless in these boundary cells.

A preliminary model (Apterous-dependent network) was presented in (see [1]), for the inter-cellular regulatory network activating Notch at the dorsal–ventral boundary in the wing imaginal disc of Drosophila. This model focussed on the cross-regulations between five genes (within and between two cells), which implements the dorsal–ventral border in the developing imaginal disc.

A refined model (complete network) was then published (see [2]) that integrates both signaling processes into a logical multivalued model encompassing four cells, i.e., a boundary and a flanking cell at each side of the boundary. Computer simulations of this model enable a qualitative reproduction of the main wild-type and mutant phenotypes described in the experimental literature. During the first signaling process, Notch becomes activated by the first signaling process in an Apterous-dependent manner. In silico perturbation experiments show that this early activation of Notch is unstable in the absence of Apterous. However, during the second signaling process, the Notch pattern becomes consolidated, and thus independent of Apterous, through activation of the paracrine positive feedback circuit of Wingless. Consequently, we propose that appropriate delays for Apterous inactivation and Wingless induction by Notch are crucial to maintain the wild-type expression at the dorsal–ventral boundary. Finally, another mutant simulation shows that cut expression might be shifted to late larval stages because of a potential interference with the early signaling process.


References

Curation
Submitter: 
D. Thieffry

The pair-rule cross-regulatory module (Sánchez and Thieffry 2003)

Summary: 

This manuscript reports a dynamical analysis of the pair-rule cross-regulatory module controlling segmentation in Drosophila melanogaster. We propose a logical model accounting for the ability of the pair-rule module to determine the formation of alternate juxtaposed Engrailed- and Wingless-expressing cells that form the (para)segmental boundaries. This module has the intrinsic capacity to generate four distinct expression states, each characterized by the expression of a particular combination of pair-rule genes or expression mode. The selection of one of these expression modes depends on the maternal and gap inputs, but also crucially on cross-regulations among pair-rule genes. The latter are instrumental in the interpretation of the maternal-gap pre-pattern. Our logical model allows the qualitative reproduction of the patterns of pair-rule gene expressions corresponding to the wild type situation, to loss-of-function and cis-regulatory mutations, and to ectopic pair-rule expressions. Furthermore, this model provides a formal explanation for the morphogenetic role of the initial bell-shaped expression of the gene even-skipped, i.e. for the distinct effects of different levels of the Even-skipped protein on its target pair-rule genes. It also accounts for the requirement of Even-skipped for the formation of all Engrailed-stripes. Finally, it provides new insights into the roles and evolutionary origins of the apparent redundancies in the regulatory architecture of the pair-rule module.

Curation
Submitter: 
D. Thieffry

Segment polarity module (Sánchez et al. 2008)

Summary: 

Initially activated by the pair-rule genes, the expression patterns of the segment polarity genes engrailed and wingless become consolidated through inter-cellular interactions between juxtaposed cells. Here, we delineate a logical model focusing on a dozen molecular components at the core of the regulatory network controlling this process. Our model analysis leads to the following conclusions: (1) the pair-rule signals, which activate engrailed and wingless genes independently of each other, need to be operative until the inter-cellular circuit involving these two genes is functional. This implies that the pair-rule pattern is instrumental both in determining the activation of the genes engrailed and wingless in rows of adjacent cells, and in consolidating these expression patterns. (2) The consolidation of engrailed and wingless expression patterns requires the proper activation of both autocrine and paracrine Wingless-pathways, as well as the full activation of the Hedgehog pathway. (3) Protein kinase A plays at least two roles through the phosphorylation of Cubitus interruptus, the effector molecule of the Hedgehog signalling pathway. (4) The roles of Sloppy-paired and Naked in the delineation of the engrailed and wingless expression domains are emphasized as being important for segmental boundary formation. Moreover, the application of an original computational method leads to the delineation of a subset of crucial regulatory circuits enabling the coexistence of specific expression states at the cellular level, as well as specific combination of cellular states inter-connected through Wingless and Hedgehog signalling. Finally, the simulation of altered expressions of segment polarity genes leads to results consistent with the published data concerning loss-of-function mutants and ectopic gene expressions. Moreover, this model makes predictions about genetic interactions that can be tested by further experiments.

Curation
Submitter: 
C. Chaouiya
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