Dynamic regulation of BMP signalling during development
The Bone Morphogenic Proteins (BMPs) represent a major, highly conserved family of growth factor signaling molecules. The BMP signaling pathway is a key regulator of a diverse array of processes, including the patterning of many different organs and tissues during embryonic development. As a consequence, misregulation of BMP signaling is associated with a range of human diseases. The primary research interest of my lab is to understand the regulation of BMP signaling and its interpretation during development, using the genetically tractable Drosophila model organism. Our research interests lie in three major areas as described below, for more information visit www.ashelab.com
1) Dynamic regulation of gene expression in response to the BMP signal
Recently, we have elucidated the BMP transcriptional network using RNA-seq and ChIP-seq, and dissected the transcription initiation mechanism for these genes using GRO-seq. Our data show that, for activation, BMP-responsive enhancers require an additional input from the Zelda pioneer transcription factor, with Zelda and Smad binding sufficient for robust activation. We have also obtained evidence that insulator proteins function at Dpp-dependent enhancers and that peak BMP responses are reduced in embryos mutant for the BEAF-32 insulator protein. Our current work focuses on understanding the dynamic regulation of Dpp target gene expression in the early embryo.
2) Extracellular regulation of BMP signalling
We have shown a key role for the collagen IV extracellular matrix protein in augmenting BMP signalling. Collagen IV acts as a scaffold to promote the interaction between BMP and its extracellular regulators to promote BMP gradient formation in the early embryo. In addition, our data suggest that collagen IV activates integrin signalling to potentiate BMP responses. In collaboration with Clair Baldock we have combined biophysical and developmental approaches to gain new mechanistic insight into the function of the Tolloid protease in BMP gradient formation. Current studies are aimed at understanding the activities of additional regulators through multidisciplinary approaches.
3) Regulation of germline stem cell fate
We have shown a role for the Brat post-transcriptional repressor in maintaining germline stem cell fate, through the regulation of specific mRNAs including those encoding BMP signal transducers. Mechanistically, this post-transcriptional repression requires the recruitment of deadenylases. We are interested in the roles of specific miRNAs in germline stem cell maintenance and the identification of additional mRNAs that are controlled by post-transcriptional repression. Additionally, we are studying features of BMP signalling and reception that allow BMPs to function at short-range to maintain germline stem cells.