Regulation of nerve growth factor and its low-affinity receptor (p75NTR) during myogenic differentiation.

In our preceding report, we have shown that nerve growth factor (NGF) and its low-affinity receptor (p75NTR) are expressed in C2C12 myoblasts and downregulated during myogenic differentiation. Furthermore, NGF affects myogenic differentiation and cell growth via p75NTR and downregulation of p75NTR is essential for myogenic differentiation (Seidl et al., 1998). Here we show that NGF and p75NTR are regulated by mechanisms preceding terminal differentiation in myogenic cells. These mechanisms include cell-density phenomena such as cell-cell contact as well as signaling of basic fibroblast growth factor (FGF-2) and its receptor (FGFR1). Downregulation of NGF and p75NTR occurred as a consequence of increasing cell density, an important trigger for the onset of myogenic differentiation. FGF-2 and FGFR1 were shown to be present in C2C12 cells and exogenous FGF-2 induced NGF and p75NTR expression, implying that FGF/FGFR signaling is an upstream regulator of the NGF/p75NTR system. The fact that FGF-2 could suspend yet not abolish density-induced downregulation indicates that cell-cell contact counteracts the FGF effect and ultimately terminates NGF/p75NTR signaling. This evidence, together with the observation that p75NTR expression is suppressed in muscle progenitors, which constitutively express adenovirus E1A proteins and thus lack the competence of myogenic differentiation, underline the important role for the NGF/p75NTR system in the interplay of multiple factors and biological systems that balance myogenic differentiation at the appropriate spatial and temporal level.