Specification of the central noradrenergic phenotype by the homeobox gene Phox2b

The closely related homeobox genes Phox2a and Phox2b are expressed in all c entral and peripheral noradrenergic neurons. Our previous results have show n that Phox2a controls the differentiation of the main noradrenergic center of the brain, the locus coeruleus, but leaves unaffected the other noradre nergic centers. Here, we report that Phox2b has a wider and overlapping rol e, in that it is required for the differentiation of all noradrenergic cent ers in the brain, including the locus coeruleus. Together with the previous ly reported lack of dopamine-b-hydroxylase and tyrosine hydroxylase express ion in the peripheral nervous system of Phox2b knock-out embryos, our prese nt findings make Phox2b a master regulator of all central and peripheral no radrenergic differentiation. We discuss the nonredundancy of Phox2 genes an d their complex partnership with the bHLH transcription factor Mash1, which is also required for the differentiation of most noradrenergic cell types.