Co-option Of Networks Research Articles

Common Themes and Future Challenges in Understanding Gene Regulatory Network Evolution.

A major driving force behind the evolution of species-specific traits and novel structures is alterations in gene regulatory networks (GRNs). Comprehending evolution therefore requires an understanding of the nature of changes in GRN structure and the responsible mechanisms. Here, we review two insect pigmentation GRNs in order to examine common themes in GRN evolution and to reveal some of the challenges associated with investigating changes in GRNs across different evolutionary distances at the molecular level. The pigmentation GRN in Drosophila melanogaster and other drosophilids is a well-defined network for which studies from closely related species illuminate the different ways co-option of regulators can occur. The pigmentation GRN for butterflies of the Heliconius species group is less fully detailed but it is emerging as a useful model for exploring important questions about redundancy and modularity in cis-regulatory systems. Both GRNs serve to highlight the ways in which redeployment of trans-acting factors can lead to GRN rewiring and network co-option. To gain insight into GRN evolution, we discuss the importance of defining GRN architecture at multiple levels both within and between species and of utilizing a range of complementary approaches.

Gene regulation of adult skeletogenesis in starfish and modifications during gene network co-option

The larval skeleton of the echinoderm is believed to have been acquired through co-option of a pre-existing gene regulatory network (GRN); that is, the mechanism for adult skeleton formation in the echinoderm was deployed in early embryogenesis during echinoderm diversification. To explore the evolutionary changes that occurred during co-option, we examined the mechanism for adult skeletogenesis using the starfish Patiria pectinifera. Expression patterns of skeletogenesis-related genes (vegf, vegfr, ets1/2, erg, alx1, ca1, and clect) suggest that adult skeletogenic cells develop from the posterior coelom after the start of feeding. Treatment with inhibitors and gene knockout using transcription activator-like effector nucleases (TALENs) suggest that the feeding-nutrient sensing pathway activates Vegf signaling via target of rapamycin (TOR) activity, leading to the activation of skeletogenic regulatory genes in starfish. In the larval skeletogenesis of sea urchins, the homeobox gene pmar1 activates skeletogenic regulatory genes, but in starfish, localized expression of the pmar1-related genes phbA and phbB was not detected during the adult skeleton formation stage. Based on these data, we provide a model for the adult skeletogenic GRN in the echinoderm and propose that the upstream regulatory system changed from the feeding-TOR-Vegf pathway to a homeobox gene-system during co-option of the skeletogenic GRN.

On the specificity of gene regulatory networks: How does network co-option affect subsequent evolution?

The process of multicellular organismal development hinges upon the specificity of developmental programs: for different parts of the organism to form unique features, processes must exist to specify each part. This specificity is thought to be hardwired into gene regulatory networks, which activate cohorts of genes in particular tissues at particular times during development. However, the evolution of gene regulatory networks sometimes occurs by mechanisms that sacrifice specificity. One such mechanism is network co-option, in which existing gene networks are redeployed in new developmental contexts. While network co-option may offer an efficient mechanism for generating novel phenotypes, losses of tissue specificity at redeployed network genes could restrict the ability of the affected traits to evolve independently. At present, there has not been a detailed discussion regarding how tissue specificity of network genes might be altered due to gene network co-option at its initiation, as well as how trait independence can be retained or restored after network co-option. A lack of clarity about network co-option makes it more difficult to speculate on the long-term evolutionary implications of this mechanism. In this review, we will discuss the possible initial outcomes of network co-option, outline the mechanisms by which networks may retain or subsequently regain specificity after network co-option, and comment on some of the possible evolutionary consequences of network co-option. We place special emphasis on the need to consider selectively-neutral outcomes of network co-option to improve our understanding of the role of this mechanism in trait evolution.

Co-option of wing-patterning genes underlies the evolution of the treehopper helmet.

Understanding the origin of novelty is a key question in evolutionary developmental biology. In arthropods, the body wall has served as a repeated source of morphological novelty. In treehoppers, an ancestrally flat part of the dorsal body wall (the pronotum) was transformed into a three-dimensional structure (the helmet), which was subsequently moulded by natural selection into diverse shapes. Here, we test three hypotheses for the developmental origin of the helmet by comparing body-region transcriptomes in a treehopper and a leafhopper that retains more ancestral morphology. In leafhoppers, pronotal gene expression is most similar to that of its serial homologue, the mesonotum. By contrast, in treehoppers, helmet gene expression is most similar to that of wings, supporting the wing-patterning network co-option hypothesis for the origin of the helmet. These results suggest that serial homologues may diverge evolutionarily through replacement of, rather than tinkering with, their ancestrally shared patterning network.

Perivascular signals alter global gene expression profile of glioblastoma and response to temozolomide in a gelatin hydrogel

Glioblastoma (GBM) is the most common primary malignant brain tumor, with patients exhibiting poor survival (median survival time: 15 months). Difficulties in treating GBM include not only the inability to resect the diffusively-invading tumor cells, but also therapeutic resistance. The perivascular niche (PVN) within the GBM tumor microenvironment contributes significantly to tumor cell invasion, cancer stem cell maintenance, and has been shown to protect tumor cells from radiation and chemotherapy. In this study, we examine how the inclusion of non-tumor cells in culture with tumor cells within a hydrogel impacts the overall gene expression profile of an in vitro artificial perivascular niche (PVN) comprised of endothelial and stromal cells directly cultured with GBM tumor cells within a methacrylamide-functionalized gelatin hydrogel. Using RNA-seq, we demonstrate that genes related to angiogenesis and extracellular matrix remodeling are upregulated in the PVN model compared to hydrogels containing only tumor or perivascular niche cells, while downregulated genes are related to cell cycle and DNA damage repair. Signaling pathways and genes commonly implicated in GBM malignancy, such as MGMT, EGFR, PI3K-Akt signaling, and Ras/MAPK signaling are also upregulated in the PVN model. We describe the kinetics of gene expression within the PVN hydrogels over a course of 14 days, observing the patterns associated with tumor cell-mediated endothelial network co-option and regression. We finally examine the effect of temozolomide, a frontline chemotherapy used clinically against GBM, on the PVN culture. Notably, the PVN model is less responsive to TMZ compared to hydrogels containing only tumor cells. Overall, these results demonstrate that inclusion of cellular and matrix-associated elements of the PVN within an in vitro model of GBM allows for the development of gene expression patterns and therapeutic response relevant to GBM.

Co-option of an Ancestral Hox-Regulated Network Underlies a Recently Evolved Morphological Novelty

The evolutionary origins of complex morphological structures such as the vertebrate eye or insect wing remain one of the greatest mysteries of biology. Recent comparative studies of gene expression imply that new structures are not built from scratch, but rather form by co-opting preexisting gene networks. A key prediction of this model is that upstream factors within the network will activate their preexisting targets (i.e., enhancers) to form novel anatomies. Here, we show how a recently derived morphological novelty present in the genitalia of D. melanogaster employs an ancestral Hox-regulated network deployed in the embryo to generate the larval posterior spiracle. We demonstrate how transcriptional enhancers and constituent transcription factor binding sites are used in both ancestral and novel contexts. These results illustrate network co-option at the level of individual connections between regulatory genes and highlight how morphological novelty may originate through the co-option of networks controlling seemingly unrelated structures.

Evolving Genital Structures: A Deep Look at Network Co-option

Novel body structures are often generated by the redeployment of ancestral components of the genome. In this issue of Developmental Cell, Glassford et al. (2015) present a thorough analysis of the co-option of a gene regulatory network in the origin of an evolutionary novelty.

Gene regulatory networks reused to build novel traits

Co-option of the eye developmental gene regulatory network may have led to the appearance of novel functional traits on the wings of flies and butterflies. The first trait is a recently described wing organ in a species of extinct midge resembling the outer layers of the midge's own compound eye. The second trait is red pigment patches on Heliconius butterfly wings connected to the expression of an eye selector gene, optix. These examples, as well as others, are discussed regarding the type of empirical evidence and burden of proof that have been used to infer gene network co-option underlying the origin of novel traits. A conceptual framework describing increasing confidence in inference of network co-option is proposed. Novel research directions to facilitate inference of network co-option are also highlighted, especially in cases where the pre-existent and novel traits do not resemble each other.