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Segmentation

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 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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