Numerous studies have investigated the formation of interhemispheric connections which are involved in high-ordered functions of the cerebral cortex in eutherian animals, including humans. The development of callosal axons, which transfer and integrate information between the right/left hemispheres and represent the most prominent commissural system, must be strictly regulated. From the beginning of their growth, until reaching their targets in the contralateral cortex, the callosal axons are guided mainly by two environmental cues: (1) the midline structures and (2) neighboring? axons. Recent studies have shown the importance of axona guidance by such cues and the underlying molecular mechanisms. In this paper, we review these guidance mechanisms during the development of the callosal neurons. Midline populations express and secrete guidance molecules, and “pioneer” axons as well as interactions between the medial and lateral axons are also involved in the axon pathfinding of the callosal neurons. Finally, we describe callosal dysgenesis in humans and mice, that results from a disruption of these navigational mechanisms. 1. Introduction Interhemispheric connections are essential components of the complex neural network in eutherian animals [1, 2]. Among such connections, the corpus callosum (CC) is the most prominent commissural connection, composed of callosal axons, in the brain. In humans, the corpus callosum consists of about 200 million axons, making it the most prominent fiber tract within the central nervous system [3, 4]. Many studies have clarified the molecular mechanism involved in the development of the CC in humans using mouse experiments [5]. Callosal neurons are mostly found in layers II/III and layer V of the cerebral cortex in rodents [6]. Recently, molecules related to the identities of the general or subtypes of cortical neurons have been disclosed. Alcamo et al. reported that Satb2, a DNA-binding protein, has a key role in the specification of callosal neurons and the formation of corticocortical connections [7]. Developmentally, callosal axons from layer V first start to project to the contralateral targets, and callosal axons from the upper layers follow the preexisting axons. After the callosal axons start to elongate, they are guided by many cues within their pathfinding route [6]. Although the importance of such cues in the development of callosal axons has been known for over 30 years [8], it still remained unclear until recently how these cues help callosal axons encountering them to project precisely to their targets. Recent
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