Reelin controls the positioning of brainstem serotonergic raphe neurons

<div><p>Serotonin (5-HT) acts as both a morphogenetic factor during early embryonic development and a neuromodulator of circuit plasticity in the mature brain. Dysregulation of serotonin signaling during critical periods is involved in developmental neurological disorders, such as schizophrenia and autism. In this study we focused on the consequences of defect <i>reelin</i> signaling for the development of the brainstem serotonergic raphe system. We observed that <i>reelin</i> signaling components are expressed by serotonergic neurons during the critical period of their lateral migration. Further, we found that <i>reelin</i> signaling is important for the normal migration of rostral, but not caudal hindbrain raphe nuclei and that <i>reelin</i> deficiency results in the malformation of the paramedian raphe nucleus and the lateral wings of the dorsal raphe nuclei. Additionally, we showed that serotonergic neurons projections to laminated brain structures were severely altered. With this study, we propose that the perturbation of canonical <i>reelin</i> signaling interferes with the orientation of tangentially, but not radially, migrating brainstem 5-HT neurons. Our results open the window for further studies on the interaction of <i>reelin</i> and serotonin and the pathogenesis of neurodevelopmental disorders.</p>