Neurofibromatosis type I (NF1) is a multi-system disease caused by mutations in the NF1 gene. NF1 encodes a RAS-GAP protein, Neurofibromin, which negatively regulates RAS signaling. Besides neuroectodermal malformations and tumours, the skeletal system is often affected in NF1 patients, scoliosis and long bone dysplasias being a main cause of considerable morbidity. Interestingly, a reduction of muscle strength and size has been reported in NF1 patients. However it remained unclear whether the observed muscle weakness was a consequence of the skeletal ramifications developing during puberty and early adulthood or if there was a muscular phenotype before the onset of a bone phenotype.
We recently demonstrated a primary defect of embryonic muscle development in a mouse model for NF1 (Kossler et al. 2011).
In-situ hybridisation for MyoD at embryonic day 13.5 demonstrating muscle patterning and size defects in the Nf1Prx1 mouse mutant. The magnifications show fore- and hindlimbs with reduction of muscle area visible e.g. for the latissimus dorsi muscle (ld), the triceps muscle (tc) or the gluteus maximus muscle (gm). Modified from Kossler et al. 2011.
This defect resulted in a continuous myopathy in Nf1Prx1 mice displaying dystrophic features such as muscle mass reduction, muscle strength reduction and connective tissue overgrowth.
At the moment, the tissue-specific contribution of Nf1 in connective tissue versus the muscle lineage is unclear. This subject is a matter of current research, where Nf1 is inactivated in a tissue-specific fashion using appropriate Cre driver lines.