FGF2 REGULATES PROLIFERATION OF NEURAL CREST CELLS, WITH SUBSEQUENT NEURONAL DIFFERENTIATION REGULATED BY LIF OR RELATED FACTORS

Two of the key early events in the development of the peripheral nervo us system are the proliferation of neural crest precursor cells and th eir subsequent differentiation into different neural cell types, We pr esent evidence that members of the fibroblast growth factor family, (F GF1 or FGF2) act directly on the neural crest cells in vitro to stimul ate proliferation in the presence of serum, These findings correlate w ith in situ hybridisation analysis, which shows FGF2 mRNA is expressed in cells both in the neural tube and within newly formed sensory gang lia (dorsal root ganglia, DRG) at embryonic day 10 in the mouse, when neural crest precursors are proliferating within the DRG, This data in fers an autocrine/paracrine loop for FGF regulation of proliferation, Evidence supporting this notion is provided by the finding that part o f the endogenous proliferative activity in the NC cultures is related to FGF, It was also found, in early neural crest cultures, that exogen ous FGF completely inhibited neuronal differentiation, probably as a d irect consequence of its mitogenic activity, In order to stimulate neu ronal differentiation significantly, it was necessary to remove the FG F and replace it with leukemia inhibitory factor (LIF) or related fact ors, Under these conditions, 50% of the cells differentiated into neur ons, which developed a sensory neuron morphology and were immunoreacti ve for the sensory markers CGRP and substance P. These data support a model of neural crest development, whereby multipotential neural crest precursor cells are stimulated to divide by FGF and subsequent develo pment into sensory neurons is regulated by LIF or other cytokines with a similar signalling mechanism.