Molecular Bases of the Reduced Osteogenic Differentiation Potential in Nf1 Deficient Osteoprogenitors
Tahaei, Seyedmohammad Ebrahim
Neurofibromatosis type 1 results from mutations in NF1, a gene that encodes Neurofibromin. This common genetic condition is associated with tibial pseudarthrosis (PA), whose etiology is unknown but thought to involve defective bone-repairing osteoprogenitors. The main objective of my thesis was to delineate the causal determinants of the poor osteogenic potential of Nf1-/- osteoprogenitors. I showed that increased Epiregulin and TGFb1 expression does not contribute to the reduced osteogenic differentiation of Nf1-/- osteoprogenitors, and contrary to all expectations, that this phenotype is likely independent from MAPK/ERK constitutive signaling. Using a RNA-Seq approach, I identified changes in pro-inflammatory and extracellular matrix gene signatures as putative determinants of the impaired differentiation of Nf1-/- osteoprogenitors. Finally, I obtained preliminary data pointing to inhibition of RUNX2 activity upon loss of Nf1 function. These results suggest unexpected interactions between Neurofibromin and proximal cell signaling/adhesion components that impact not one but multiple downstream signaling pathways.