Defining BMP-activated genetic networks during neural tissue development in Drosophila

• Applicant: Dr. Helen Neuert
• Subject Area: Developmental Biology ; General Genetics and Functional Genome Biology
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 409626532

Bone Morphogenetic Proteins (BMP) direct developmental, functional and regenerative processes in most cell types. Disrupted BMP signaling contributes to cancers, fibroses and debilitating disorders in most tissues. Work in the fruitfly Drosophila has shown that target-derived BMP signaling is essential for nervous system function, ensuring motoneuron synaptic growth, stability and neurotransmission. BMP signaling acts via Smad transcription factors, which bind noncoding DNA at BMP-responsive cis-regulatory elements (BMP-REs). These BMP-REs are the entry point for control of BMP-dependent cellular events. As BMP-REs and the genes they regulate are largely unknown for most cellular processes, we do not understand the critical molecular events that underlie these BMP-regulated cellular processes that have been implicated in a variety of neurological disorders. The Allan lab has developed bioinformatics tools, based on the detection of two BMP-RE sequence motifs, for BMP-RE discovery in Drosophila. They predict a statistically-enriched set of 861 BMP-REs within 50kb of 415 BMP-activated genes in the BMP-dependent process of neuronal synaptic function. In vivo validation of 62 BMP-REs to date demonstrated that 61% are indeed functional. These methods also predict BMP-RE enrichment around BMP-responsive genes in vertebrates, so the methods can likely be applied to mammals. My goal is to use unbiased genomics methods to discover BMP-REs and BMP-regulated genes that govern synaptic function in Drosophila motoneurons. My studies will provide a validation rate for bioinformatics predictions and identify the full complement of DNA sequences that can function as Smad-binding BMP-REs – for the expansion of our ability to predict BMP-REs in the fly and mammalian genome. Large-scale BMP-RE identification will open the door to detailed analysis of the gene regulatory mechanisms at the core of BMP-dependent cellular processes underlying disastrous diseases and neurological disorders.

• DFG Programme: Research Fellowships
• International Connection: Canada
• Host: Douglas Allan, Ph.D.