Segmentation

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.

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.