THE ERBB2 AND ERBB3 RECEPTORS AND THEIR LIGAND, NEUREGULIN-1, ARE ESSENTIAL FOR DEVELOPMENT OF THE SYMPATHETIC NERVOUS-SYSTEM

Neuregulins (NDF, heregulin, GGF ARIA, or SMDF) are EGF-like growth an d differentiation factors that signal through tyrosine kinase receptor s of the ErbB family. Here, we report a novel phenotype in mice with t argeted mutations in the erbB2, erbB3, or neuregulin-1 genes. These th ree mutations cause a severe hypoplasia of the primary sympathetic gan glion chain. We provide evidence that migration of neural crest cells to the mesenchyme lateral of the dorsal aorta, in which they different iate into sympathetic neurons, depends on neuregulin-1 and its recepto rs. Neuregulin-1 is expressed at the origin of neural crest cells. Mor eover, a tight link between neuregulin-1 expression, the migratory pat h, and the target site of sympathogenic neural crest cells is observed . Sympathetic ganglia synthesize catecholamines in the embryo and the adult. Accordingly, catecholamine levels in mutant embryos are severel y decreased, and we suggest that the lack of catecholamines contribute s to the embryonal lethality of the erbB3 mutant mice. Thus, neureguli n-1, erbB2, and erbB3 are required for the formation of the sympatheti c nervous system; the block in development observed in mutant mice is caused by a lack of neural crest precursor cells in the anlage of the primary sympathetic ganglion chain. Together with previous observation s, these findings establish the neuregulin signaling system as a key r egulator in the development of neural crest cells.