Polarity Regulation in Migrating Neurons in the Cortex Orly Reiner & Tamar Sapir Received: 28 January 2009 / Accepted: 12 March 2009 / Published online: 28 March 2009 # Humana Press Inc. 2009 Abstract The formation of the cerebral cortex requires migration of billions of cells from their birth position to their final destination. A motile cell must have internal polarity in order to move in a specified direction. Locomotory polarity requires the coordinated polymeriza- tion of cytoskeletal elements such as microtubules and actin combined with regulated activities of the associated molecular motors. This review is focused on migrating neurons in the developing cerebral cortex, which need to attain internal polarity in order to reach their proper target. The position and dynamics of the centrosome plays an important function in this directed motility. We highlight recent interesting findings connecting polarity proteins with neuronal migration events regulated by the microtubule- associated molecular motor, cytoplasmic dynein. Keywords Neuronal migration . Brain development . LIS1 . DCX . MARK2 . Par-1 . Polarity proteins . Centrosome . Microtubules . Actin Neuronal Migration in the Cerebral Cortex Neuronal migration is a necessary process required for proper brain architecture since most neurons are born in a position different from which they will reside in. The six layers of the cerebral cortex are composed of neurons that are born in different areas but are subsequently organized according to their birthdating [1, 2]. Neurons born relatively late during corticogenesis reside in more super- ficial layers on top of the older neurons, thus composing an inside-out organization. Neurons reach their target destina- tion using different modes of migration. Neurons born in the germinal zones of the dorsal telencephalon migrate towards the pial surface of the cortex in a radial path. These neurons are the pyramidal or the excitatory neurons of the cerebral cortex. Neurons migrating along this route attach to radial glia, which provide a transient scaffold for directed migration [3–5]. Live cell imaging and in utero electro- poration experiments have revealed that neurons undergo dramatic morphological changes during migration. During most of their migratory route, they exhibit a bipolar structure with a leading edge directed towards the pial surface and a trailing process pointed to the ventricular surface (Fig. 1). Within the subventricular zone and lower intermediate zone, an additional transient multipolar stage has been detected. This multipolar stage was described in several types of neurons as well as in neocortical neurons as a transient step preceding the migration along radial glia [6]. Neurons migrating along radial glia exhibit a bipolar structure, and once these neurons reach the pial surface, they detach from the radial glia and continue to move towards their correct laminar position. Abnormal Neuronal Migration Deficits in neuronal migration in humans and in mice have provided us with insights on the regulatory mechanisms involved in this process. Abnormal neuronal migration may result in cortical malformations that are responsible for a significant proportion of cases of mental retardation and epilepsy in children [7–9]. Lissencephaly (i.e., smooth brain) is a severe human neuronal migration disorder. Mol Neurobiol (2009) 40:1–14 DOI 10.1007/s12035-009-8065-0 O. Reiner (*) : T. Sapir Department of Molecular Genetics, The Weizmann Institute of Science, 76100 Rehovot, Israel e-mail: orly.reiner@weizmann.ac.il