Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant disease caused by mutations in the NF1 tumor suppressor gene, which affect approximately 1 out of 3000 individuals. Patients with NF1 suffer from a range of malignant and nonmalignant manifestations such as plexiform neurofibromas and skeletal abnormalities. We previously demonstrated that Nf1 haploinsufficiency in mesenchymal stem/progenitor cells (MSPCs) results in impaired osteoblastic differentiation, which may be associated with the skeletal manifestations in NF1 patients. Here we sought to further ascertain the role of Nf1 in modulating the migration and adhesion of MSPCs of the Nf1 haploinsufficient (Nf1+/−) mice. Nf1+/− MSPCs demonstrated increased nuclear-cytoplasmic ratio, increased migration, and increased actin polymerization as compared to wild-type (WT) MSPCs. Additionally, Nf1+/− MSPCs were noted to have significantly enhanced cell adhesion to fibronectin with selective affinity for CH271 with an overexpression of its complimentary receptor, CD49e. Nf1+/− MSPCs also showed hyperactivation of phosphoinositide 3-kinase (PI3-K) and mitogen activated protein kinase (MAPK) signaling pathways when compared to WT MSPCs, which were both significantly reduced in the presence of their pharmacologic inhibitors, LY294002 and PD0325901, respectively. Collectively, our study suggests that both PI3-K and MAPK signaling pathways play a significant role in enhanced migration and adhesion of Nf1 haploinsufficient MSPCs.
Highlights
Neurofibromatosis type 1 (NF1), known as Von Recklinghausen’s disease, is an autosomal dominant disorder with an incidence of 1 in 3000 live births [1]
Cells were stained with 400 nM fluorescein isothiocyanate(FITC)-phalloidin and DAPI; (B) A quantitative comparison of nuclear-cytoplasmic ratio between WT and Nf1+/− mesenchymal stem/progenitor cells (MSPCs) based on the average ratio of nuclear area/cytoplasm area in 50 cells/field from five different fields
Data are represented as mean ± SD from three batches of MSPCs isolated from individual mice (* p < 0.05 for Nf1+/− vs. WT MSPCs)
Summary
Neurofibromatosis type 1 (NF1), known as Von Recklinghausen’s disease, is an autosomal dominant disorder with an incidence of 1 in 3000 live births [1]. NF1 is one of the most common genetic disorders with a predilection toward neoplasms, which include astrocytomas, pheochromocytomas, myeloid leukemia, and the pathognomonic cutaneous and plexiform neurofibromas [2]. In addition to these neoplastic conditions, NF1 patients variably experience skeletal deformations, hyperpigmentation of the skin (café-au-lait macules), benign lesions of the iris (Lisch nodules), and intellectual deficits [3,4]. The neurofibromin GAP domain controls the conversion of Ras-GTP to its inactive GDP-bound state, thereby negatively regulating the activity of downstream signaling pathways, including the mitogen activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3-K) pathways. Loss of one or both alleles of NF1 leads to aberrant Ras-dependent cellular functions including proliferation, differentiation, migration, and survival, in multiple cell lineages [5,6]
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