Developing tissues are patterned by coordinated activities of signaling systems, which can be integrated by a regulatory region of a gene that binds multiple transcription factors or by a transcription factor that is modified by multiple enzymes. Based on a combination of genetic and imaging experiments in the early Drosophila embryo, we describe a signal integration mechanism that cannot be reduced to a single gene regulatory element or a single transcription factor. This mechanism relies on an enzymatic network formed by mitogen-activated protein kinase (MAPK) and its substrates. Specifically, anteriorly localized MAPK substrates, such as Bicoid, antagonize MAPK-dependent downregulation of Capicua, a repressor that is involved in gene regulation along the dorsoventral axis of the embryo. MAPK substrate competition provides a basis for ternary interaction of the anterior, dorsoventral, and terminal patterning systems. A mathematical model of this interaction can explain gene expression patterns with both anteroposterior and dorsoventral polarities.
Bibliographical noteFunding Information:
We thank Ze'ev Paroush, Eric Wieschaus, Mathieu Coppey, Oliver Grimm, Trudi Schüpbach, Christine Rushlow, Ulrike Löhr, and members of the Shvartsman laboratory for multiple helpful discussions. We thank Trudi Schüpbach, Christine Rushlow, Natalie Dostatni, Steve Hanes, Johannes Jaeger, Kim Rittenhouse, and Oliver Grimm for reagents used in this work. S.Y.S. acknowledges partial support by NSF via grant DMS-0718604, as well as P50 GM071508 and RO1 GM078079 grants from the NIH. G.J. acknowledges support by ICREA by grants from MICINN (BFU2008-01875) and AGAUR (2009SGR-1075). H.L. was supported by NSF DBI-0649833, NIH NS058465, Sloan Foundation, and DuPont Foundation. C.A.B. was supported by R01-GM45248 grant from the NIH.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Biochemistry, Genetics and Molecular Biology(all)
- Developmental Biology
- Cell Biology