Molecular and genetic analysis of developmental gene regulatory networks.

摘要

Networks of interacting regulatory genes control cell fate specification, differentiation, and patterning to generate and localize different cell types during embryogenesis and generate a developing individual. These gene regulatory networks (GRNs) integrate cell identity with spatial, temporal, and positional cues to enable a series of logic-based changes in gene activity to coherently direct development. To ensure robust and reproducible network behavior, developmental GRNs rely on characteristic network substructures, called modules or motifs, to perform specific functions. These modules consist of small groups of genes, and interactions both within and between modules specify the activity state of downstream genes when cells transition from one identity state to the next. In this way, modular interactions determine the subsequent regulatory state of the cell. I have studied the GRN that operates during the specification of C lineage cells, which produce epidermis and muscle in the nematode C. elegans. A multi-component positive feedback loop composed of pal-1, tbx-8 and tbx-9 functions early in C lineage specification to commit cells to the C lineage fate. Positive regulatory interactions between the three genes generate a self-reinforcing loop that allows the activation of downstream components in the C lineage gene regulatory network. Once cells have been committed to adopting the C lineage identity, the deployment of two antagonistic cell-type specification modules for epidermis and muscle development is regulated by a Wnt signaling pathway that is differentially active in sister cells that adopt either epidermal or muscle cell fates. This allows the reproducible specification of skin and muscle cells from common progenitors in the C lineage. As network behaviors are often repeated within and across species, the elucidation of this C lineage GRN should provide useful insights into other developmental GRNs both in C. elegans and other organisms.