DCC is required for the tangential migration of noradrenergic neurons in locus coeruleus of mouse brain.

The tangential migration from the dorsal rhombomere (r) 1 to the dorsolateral pontine tegmentum is a crucial event in the development of locus coeruleus (LC), but the molecular mechanisms underlying the migration are not well understood. We show that the Netrin receptor DCC is expressed in LC neurons and is required for their tangential migration. In DCC(-/-) embryos, fate determination of LC neurons appeared normal but tangential migration failed to initiate properly. Although many LC neurons eventually reached the dorsolateral pontine tegmentum in DCC(-/-) embryos at late embryonic stages, a substantial number of LC neurons were abnormally distributed in the rostral pons and cerebellum. In DCC(kanga) mice that lack the intracellular P3 domain of DCC, these defects were not observed. In addition, although Unc5h3, another Netrin receptor, was expressed in the dorsal r1, Unc5h3(-/-) mice exhibited the normal LC morphology and gene expression profiles in the LC compared with wild-type mice. Thus, our findings demonstrate that DCC is a key regulator of tangential migration of LC neurons during the embryonic development.