Feedback Control of Gene Expression in Tissue Patterning

Receptor-mediated signals are crucial for tissue patterning in development, stem cell maintenance, and adult homeostasis. Many diseases, most notably cancer, occur when cells misinterpret or ignore signals regarding proliferation, migration, and/or apoptosis, implying these signaling pathways must be tightly regulated. Since these same signals are highly conserved between species, we study the regulation of signaling pathways in the context of patterning the dorsal-ventral (DV) axis in the early Drosophila melanogaster embryo.

The transcription factor Dorsal, homologous to NFκB, is responsible for expression of the genes that generate the DV pattern in the Drosophilaembryo. Dorsal is present in the nuclei in a gradient, with the highest concentration at the ventral midline and a steady decay to about 40% of the embryo’s circumference. This gradient is established on the ventral side of the embryo by signaling through the Toll receptor, which phosphorylates the inhibitor protein Cactus (homologous to I-κB), marking it for degradation. In the absence of Cactus, Dorsal is free to enter the nuclei and direct expression of target genes in a concentration-dependent manner.

Because the Dorsal gradient is essential to correct patterning of the early embryo, there must be multiple sets of regulatory loops to ensure proper development in the face of perturbed conditions. Preliminary evidence indicates the existence of such feedback loops through Cactus, Toll, or other receptor-mediated signaling networks. Here we present work on a negative feedback loop that acts to stabilize the Dorsal gradient and minimize patterning defects in the face of large changes in input parameters.