Semaphorin 4D regulates gonadotropin hormone-releasing hormone-1 neuronal migration through PlexinB1-Met complex

In mammals, reproduction is dependent on specific neurons secreting the neuropeptide gonadotropin hormonereleasing hormone-1 (GnRH-1). These cells originate during embryonic development in the olfactory placode and migrate into the forebrain, where they become integral members of the hypothalamic- pituitary-gonadal axis. This migratory process is regulated by a wide range of guidance cues, which allow GnRH-1 cells to travel over long distances to reach their appropriate destinations. The Semaphorin4D (Sema4D) receptor, PlexinBl, is highly expressed in the developing olfactory placode, but its function in this context is still unknown. Here, we demonstrate that PlexinBl - deficient mice exhibit a migratory defect of GnRH-1 neurons, resulting in reduction of this cell population in the adult brain. Moreover, Sema4D promotes directional migration in GnRH-1 cells by coupling PlexinBl with activation of the Met tyrosine kinase (hepatocyte growth factor receptor). This work identifies a function for PlexinBl during brain development and provides evidence that Sema4D controls migration of GnRH-1 neurons. © 2008 Giacobini et al.