Defining common mechanisms that guide tangential neuronal migration in the mammalian brain. (360G-Wellcome-089775_Z_09_Z)

Neuronal migration plays an essential role in organising the brain into functional domains. Two distinct modes of neuronal migration have been identified in the developing forebrain: radial and tangential. Three distinct neuronal systems in the forebrain exhibit the tangential mode of migration: cortical interneurons, gonadotropin-releasing hormone (GnRH) neurons and interneuron progenitors of the olfactory bulb. We have been investigating for some time the molecular mechanisms that guide cortic al interneurons and have more recently begun to study the migration of the GnRH neurons. Our work raises the possibility that similar molecular guidance mechanisms control movement of both types of neurons. Here, we propose interrelated lines of investigation to study the involvement of two classes of chemorepulsive molecules (slits and semaphorins) and their corresponding receptors (robos and neuropilins) in the migration of all three neuronal systems. Further, we intend to study how these mole cules interact functionally to orchestrate the complex migratory behaviour of these neurons. The proposed research programme will elucidate novel mechanisms in tangential neuronal migration and shed light on the aetiology of some neuronal migration disorders in humans.