Master regulators in development: Views from the Drosophila retinal determination and mammalian pluripotency gene networks

Abstract

Among the mechanisms that steer cells to their correct fate during normal development, master regulatory networks are unique in their sufficiency to trigger a developmental program outside of its normal context. In this review we discuss the key features that underlie master regulatory potency during normal and ectopic development, focusing on two examples, the retinal determination gene network (RDGN) that directs eye development in the fruit fly and the pluripotency gene network (PGN) that maintains cell fate competency in the early mammalian embryo. In addition to the hierarchical transcriptional activation, extensive positive transcriptional feedback, and cooperative protein-protein interactions that enable master regulators to override competing cellular programs, recent evidence suggests that network topology must also be dynamic, with extensive rewiring of the interactions and feedback loops required to navigate the correct sequence of developmental transitions to reach a final fate. By synthesizing the in vivo evidence provided by the RDGN with the extensive mechanistic insight gleaned from the PGN, we highlight the unique regulatory capabilities that continual reorganization into new hierarchies confers on master control networks. We suggest that deeper understanding of such dynamics should be a priority, as accurate spatiotemporal remodeling of network topology will undoubtedly be essential for successful stem cell based therapeutic efforts.

Amphioxus photoreceptors - insights into the evolution of vertebrate opsins, vision and circadian rhythmicity

“…These were shown to be innervated by the 1 st DO (Lacalli, 2002). Several studies focused on transcription factors known to be involved in development of vertebrate and invertebrate visual systems, such as the members of the Drosophila retinal determination gene network (RDGN) (Davis and Rebay, 2017). Expression of amphioxus RDGN orthologous genes belonging to Pax, Six, Eya and Dach families, respectively, was investigated by whole mount in situ hybridization at various stages of embryonic development.…”

A single cell transcriptional roadmap for cardiopharyngeal fate diversification

“…Therefore, whereas Tbx1 could in principle contribute to Dach1 expression, we must invoke other mechanisms accounting for its early widespread expression and selective maintenance in the SHF. Notably, together with Pax , Six and Eya family genes, Dach homologs form a conserved "retinal network" (Davis and Rebay, 2017;Kumar, 2009) . In the mouse, Six and Eya homologs have been implicated in early SHF development (Guo et al, 2011;Zhou et al, 2017) , opening the possibility that conserved elements of the retinal network contribute to SHF-specific gene expression.…”

Regulatory network analysis of Paneth cell and goblet cell enriched gut organoids using transcriptomics approaches

“…Some of these regulators were predicted to be important in both cell types, but exhibited differential targeting patterns between the PCeE and the GCeE networks, indicating rewiring of regulators between the cell types. This highlights apparent redundancy and/or cooperation of regulators which control similar cell type specific functions and shows the potential importance of regulatory rewiring in the evolution of cell type specific pathways and functions, something which has been shown previously to occur (83,84). Functional analysis of the targets of the most rewired regulators (Etv4, let-7e-5p, miR-151-3p, Myb and Rora) highlights an overrepresentation of metabolism associated targets in the PCeE network and cell cycle associated targets in the GCeE network.…”