Formation of brainstem (nor)adrenergic centers and first-order relay visceral sensory neurons is dependent on homeodomain protein Rnx/Tlx3

Brainstem visceral sensory and (nor)adrenergic neurons play crucial roles i n modulating cardiovascular and respiratory functions. The origins and form ation of these neurons are poorly understood. Here we show that these two c lasses of neurons are derived from Mash1-positive precursor cells, and can be prospectively identified by combinatorial expression of two homeobox gen es, Rnx and Phox2 (Phox2a or Phox2b). It was previously shown that Rnx-defi cient mice die from respiratory failure. Here we show that Rnx function is required for formation of first-order relay visceral sensory neurons in the brainstem. In addition, as in Phox2b-deficient mice, the development of mo st (nor)adrenergic centers is compromised in Rnx mutants. We also provide g enetic evidence to show that Rnx and Phox2 proteins may function independen tly to specify the (nor)adrenergic phenotype. Out studies reveal a surprisi ng ontogenetic relationship between relay visceral sensory and (nor)adrener gic neurons, and suggest that it may be a common theme in the developing ne rvous system that the same set of transcriptional regulators is associated with formation of multiple components within a neuronal network.