Specificity of Notch pathway activation: Twist controls the transcriptional output in adult muscle progenitors

Abstract

SUMMARYCell-cell signalling mediated by Notch regulates many different developmental and physiological processes and is involved in a variety of human diseases. Activation of Notch impinges directly on gene expression through the Suppressor of Hairless [Su(H)] DNA-binding protein. A major question that remains to be elucidated is how the same Notch signalling pathway can result in different transcriptional responses depending on the cellular context and environment. Here, we have investigated the factors required to confer this specific response in Drosophila adult myogenic progenitor-related cells. Our analysis identifies Twist (Twi) as a crucial co-operating factor. Enhancers from several direct Notch targets require a combination of Twi and Notch activities for expression in vivo; neither alone is sufficient. Twi is bound at target enhancers prior to Notch activation and enhances Su(H) binding to these regulatory regions. To determine the breadth of the combinatorial regulation we mapped Twi occupancy genome-wide in DmD8 myogenic progenitor-related cells by chromatin immunoprecipitation. Comparing the sites bound by Su(H) and by Twi in these cells revealed a strong association, identifying a large spectrum of co-regulated genes. We conclude that Twi is an essential Notch co-regulator in myogenic progenitor cells and has the potential to confer specificity on Notch signalling at over 170 genes, showing that a single factor can have a profound effect on the output of the pathway.

Notch cooperates with Lozenge/Runx to lock haemocytes into a differentiation programme

“…In addition, Kc cells differ substantially from the muscle-related DmD8 cells (Fig. 1D) (Cherbas et al, 2011), where Notch activity is involved in maintaining progenitor characteristics in collaboration with transcription factor Twist (Bernard et al, 2010), enabling us to discover how the Notch response differs between cell types.…”

Bidirectional Notch activation represses fusion competence in swarming adultDrosophilamyoblasts

“…Notch signaling maintains the transit-amplifying state Notch signaling has been implicated in the context of adult myogenesis in Drosophila (Anant et al, 1998;Bernard et al, 2006;Bernard et al, 2010). An interesting feature is that Notch signaling is active in most wing disc-derived myoblasts, but is shut down in a small number of those myoblasts that are in close proximity to the myotubes (Bernard et al, 2006).…”

Signalling Pathways in Development and Human Disease: A Drosophila Wing Perspective

“…At this time, little is known about the number and identity of target genes whose expression are directly regulated by signalling and whose function contributes significantly to the cellular response to signalling. This is an area of intensive research, and the use of chromatin immunoprecipitation techniques coupled with microarrays or deep-sequencing, the development of reporter systems for cell culture assays and the functional analysis of the identified target genes promise a much better understanding of the transcriptional responses to signalling in the near future (Yang et al, 2004;Miyazono et al, 2005;Friedman and Perrimon, 2006;Mummery-Widmer et al, 2009;Bernard et al, 2010;Kim and Marques, 2010).…”