(682h) Nuclear Trapping of Cactus in the Early Drosophila Embryo May Modulate the Effective Concentration of Transcription Factor Dorsal

For more than 60 years, biologists have been investigating the chemical basis for the establishment of positional information within biological tissues, known as morphogenesis. During morphogenesis a transcription factor forms a gradient across a tissue and induces differential gene expression in a concentration-dependent fashion. Concentration-dependent gene expression initiates tissue-specific chain reactions that lead to cell differentiation and the establishment of distinct body structures.

Dorsoventral axis patterning in the early Drosophila embryo is controlled by transcription factor Dorsal (dl). A homologue of the mammalian transcription factor NF-kB, dl is ubiquitously inhibited from regulating gene expression by the inhibitor protein Cactus (Cact). Signaling through the Toll receptor along the ventral side of the embryo causes Cact degradation and nuclear uptake of unbound dl protein. Once dl becomes localized to the nucleus, it can promote or inhibit its target genes, including Snail (sna), Ventral Neuroblasts Deffective (vnd),  Short Gastrulation (sog), and Decapentaplegic (dpp).

The working model of dl gradient formation has changed very little since its discovery in the late 1980s, despite tremendous advances in our quantitative understanding of the dynamics involved. However, the most recently published in silico model of dl gradient dynamics fails to capture many important temporal features seen in the live-embryo imaging study published by Reeves et al. (2012). We propose a new model of dl/Cact dynamics that incorporates the trapping of both dl and Cact by the reforming, post-mitotic nuclear envelopes that shows excellent agreement with the results of live imaging.

This new model of dl gradient formation also provides a convenient explanation for the outstanding question of how dl can regulate the expression of genes, such as vnd, sog and dpp,  where its signal-to-noise ratio is very low. According to our results, nuclear Cact may act to attenuate any detrimental effects stochasticity would have on dl’s ability to accurately specify domains of gene expression. By isolating the dynamics of free (transcriptionally-active) dl in silico, we are able to simulate dl-mediated gene expression that shows excellent agreement with published results, inspite of the presence of high signal noise.