970C Poster - 15. Models of human disease
Saturday April 09, 1:30 PM - 3:30 PM

Authors:
Connor N. Broyles; Valentina Botero; Seth M. Tomchik

Affiliation: Department of Neuroscience, The Scripps Research Institute, Scripps Florida, Jupiter, FL, USA.

Keywords:
k. developmental disorders; t. other (Neural Developmental Disorders)

Neurofibromatosis type 1 (NF1) is a chronic multisystem genetic disorder affecting approximately 1 in 3,500 humans. NF1 patients often experience multiple symptoms such as tumors, cognitive dysfunction, sleep disturbances, and metabolic changes. NF1 is caused by mutations in the NF1 gene, which encodes a protein called neurofibromin. One of the major biochemical functions of neurofibromin is Ras GAP activity, which downregulates Ras signaling. Loss of function of the catalytic neurofibromin GAP-related domain, which is responsible for neurofibromin’s Ras GAP activity, is a major contributor to NF1 phenotypes such as increased energy expenditure. In addition, Ras-independent effects on other signaling pathways, such as cAMP/PKA, have been described for phenotypes like short stature and sleep disruption. The impacts on relatively pleiotropic cellular signaling pathways, as well as the systemic interactions among different cell types, raises the question of how loss of neurofibromin drives systemic and organismal pathophysiology in NF1. Downstream molecular pathways remain elusive. This study aims to identify key pathways involved in NF1 pathology using a transcriptomics approach.

Loss of neurofibromin may drive effects on organismal physiology via alterations in the transcription of downstream gene products. To gain insight into the transcriptional landscape in NF1, we have examined the effects of loss of neurofibromin on gene expression in Drosophila. RNA sequencing was used to identify differentially expressed genes (DEGs) in Nf1 mutants (NF1^P1) as compared to wild-type controls (w^CS10). RNA from heads and bodies was compared between mutants and controls to identify DEGs in neuronally-enriched samples vs. the rest of the body. Analyses revealed several classes of dysregulated transcripts in NF1 mutants; specific for heads/bodies or shared in both. Gene ontology analysis revealed several enriched processes and pathways in NF1 mutants, with association to known human phenotypes, and follow-up genetic experiments are narrowing key pathways for NF1 effects on organismal phenotypes.