REGULATION OF NERVE GROWTH-FACTOR AND ITS LOW-AFFINITY RECEPTOR (P75(NTR)) DURING MYOGENIC DIFFERENTIATION

In our preceding report, we have shown that nerve growth factor (NGF) and its low-affinity receptor (p75(NTR)) are expressed in C2C12 myobla sts and downregulated during myogenic differentiation. Furthermore, NG F affects myogenic differentiation and cell growth via p75(NTR) and do wnregulation of p75(NTR) is essential for myogenic differentiation (Se idl et al., 1998). Here we show that NGF and p75(NTR) are regulated by mechanisms preceding terminal differentiation in myogenic cells. Thes e 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 p75(NTR) occurred as a co nsequence of increasing cell density, an important trigger for the ons et of myogenic differentiation. FGF-2 and FGFR1 were shown to be prese nt in C2C12 cells and exogenous FGF-2 induced NGF and p75(NTR) express ion, implying that FGF/FGFR signaling is an upstream regulator of the NGF/p75(NTR) system. The fact that FGF-2 could suspend yet not abolish density-induced downregulation indicates that cell-cell contact count eracts the FGF effect and ultimately terminates NGF/p75(NTR) signaling . This evidence, together with the observation that p75(NTR) expressio n is suppressed in muscle progenitors, which constitutively express ad enovirus E1A proteins and thus lack the competence of myogenic differe ntiation, underline the important role for the NGF/p75(NTR) system in the interplay of multiple factors and biological systems that balance myogenic differentiation at the appropriate spatial and temporal level . (C) 1998 Wiley-Liss, Inc.