title: Modeling the precision and robustness of Hunchback border during Drosophila embryonic development.
abstract: During anterior-posterior axis specification in the Drosophila embryo, the Hunchback (Hb) protein forms a sharp boundary at the mid-point of the embryo with great positional precision. While Bicoid (Bcd) is a known upstream regulator for hb expression, there is evidence to suggest that Hb effectively filters out "noisy" data received from varied Bcd gradients. We use mathematical models to explore simple regulatory networks which filter out such noise to produce a precise Hb boundary. We find that in addition to Bcd and Hb, at least one freely evolving protein is necessary. An automated search yields a number of examples of three-protein networks exhibiting the desired precision. In all such networks, Hb diffuses much slower than the third protein. In addition, the action of Hb on the third protein is the opposite of the action of the third protein on hb (i.e. if Hb activates the third protein, then the third protein inhibits hb expression, and vice versa). Most of the discovered systems satisfy the known biological properties, that Bcd activates hb, and that Hb activates its own expression. We find that all network topologies satisfying these constraints arise among the networks exhibiting the desired precision. Investigating the dynamics of these networks, we find that under a general class of non-uniform initial conditions, Bcd can be eliminated from the system and the spatiotemporal evolution of these two proteins alone is sufficient to recapture the dynamics. We hypothesize that Bcd is needed only to spatially disturb the gradient of the third protein, and then becomes unnecessary in the further evolution of the Hb border. This provides a possible explanation as to why the Hb dynamics are robust under perturbations of the Bcd gradient. Under this hypothesis, other proteins would be able to assume the role of Bcd in our simulations (possibly in the case of evolutionary divergences or a redundancy in the process), with the only constraint that they act to positively regulate hb.
authors.affiliation: Department of Mathematics, Rice University, 6100 S. Main, Houston, TX 77005, USA. hardway@rice.edu
authors.forename: Heather
authors.initials: H
authors.lastname: Hardway
authors.forename: Bibhash
authors.initials: B
authors.lastname: Mukhopadhyay
authors.forename: Timothy
authors.initials: T
authors.lastname: Burke
authors.forename: Theron
authors.initials: T
authors.lastname: James Hitchman
authors.forename: Robin
authors.initials: R
authors.lastname: Forman
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics; D003198:Computer Simulation; D004268:DNA-Binding Proteins / Q000235:genetics*; D004330:Drosophila / Q000196:embryology*; D029721:Drosophila Proteins / Q000235:genetics*; D004625:Embryo, Nonmammalian / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000235:genetics; D009024:Morphogenesis / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D018398:Homeodomain Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C056478:bcd protein, Drosophila; C061245:hb protein, Drosophila