Patterns of neuronal migration in the embryonic cortex Arnold R. Kriegstein 1,2 and Stephen C. Noctor 1 1 Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA 2 Department of Pathology, and the Center for Neurobiology and Behavior, Columbia University Medical Center, New York, NY 10032, USA Real-time imaging of migrating neurons has changed our understanding of how newborn neurons reach their final positions in the developing cerebral cortex. The migratory routes and modes of migration are more diverse and complex than previously thought. The find- ing that cortical interneurons migrate to the cortex from origins in the ventral telencephalon has already markedly altered our view of cortical migration. More recent findings have demonstrated additional nuances in the migratory pattern and highlighted differences between subsets of interneurons. Moreover, radial migration of pyramidal neurons does not progress smoothly from ventricle to cortical plate, but is instead characterized by distinct migratory phases in which neurons change shape and direction of movement. Inte- grating these findings with the molecular machinery underlying migration will provide a more complete pic- ture of how the cerebral cortex is assembled. A curious feature of brain development is that, although neurons are generated from precursor cells that line the walls of the ventricular system deep within the brain, newborn neurons often migrate long distances from their birthplace to reach their final destinations. This is particularly evident in the process of cortical development, whereby newborn neurons must migrate to the outer surface of the developing cortex. At early stages, when the cortical anlage is small, these distances are short but as development proceeds the distances that neurons must migrate becomes progressively longer, and in the case of the primate brain can reach distances up to 7 mm [1]. Studies of granule cell migration in the developing cerebellum have provided insights into some of the mechanisms of neuronal migration [2–4]. Recently, with the application of molecular and genetic approaches to the study of migration disorders in humans and in mutant mice, many key gene products have been discovered that are involved in neuronal migration [2,5 – 7]. Given the interactive nature of the process of migration, it is not surprising that these molecules include receptors, transcription factors, adhesion molecules, extracellular matrix proteins, diffusible and intracellular signaling molecules, and components of associated signaling cascades. The focus of the current review, however, is to describe recent advances in understanding the patterns of neuronal migration in the developing cerebral cortex. Studies based largely on real- time imaging of migrating neurons in situ in both rodent and primate cortex have contributed significantly to a more complete description of the routes that neurons take to reach their proper positions and provide a framework into which the molecular steps can be integrated. Dynamics of cortical assembly The first postmitotic cortical neurons collect in an outside- in sequence to form a transient layer termed the preplate [8]. Subsequently-born neurons migrate into the preplate to form a new series of layers collectively known as the cortical plate, which thereby splits the preplate into a superficial layer, the marginal zone, and a deeper layer, the subplate. As additional waves of migrating neurons arrive in the cortical plate they bypass earlier-generated neurons to form the cortical layers in an inside-out sequence; deeper layers are the first to form, superficial layers the last [9]. The correlation of laminar fate with birth order holds for all cortical neurons, including pyramidal neurons that constitute the principle projection neurons, and interneurons that are primarily inhibitory local circuit neurons [10–12]. Recent studies probing the sites of origin and mode of migration of cortical neurons have demonstrated that whereas cortical pyramidal neurons are generated in the germinal zones of the dorsal telencephalon [13–15], most, if not all, cortical inter- neurons are generated in the ventral telencephalon [16–19]. The latter region includes the proliferative zones of the ganglionic eminence. Thus, cortical pyramidal neurons can generally follow a relatively direct radial path to their laminar position in the developing cortex, but interneurons must travel circuitously and traverse a greater distance (Figure 1). The migratory routes of neurons arising in both the dorsal and ventral telence- phalon have been the subject of intense study. Recent observations, although still falling short of providing a complete picture, indicate that migration patterns are complex, characterized by spatially and temporally dis- tinct changes in the direction of movement and speed of migration for both pyramidal cells and interneurons. Non-cortical origin of cortical interneurons Recent studies have demonstrated that many cortical interneurons originate in the basal ganglia primordia – Corresponding author: Arnold R. Kriegstein (ark17@columbia.edu). Available online 20 May 2004 Review TRENDS in Neurosciences Vol.27 No.7 July 2004 www.sciencedirect.com 0166-2236/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2004.05.001