The development of the corpus callosum depends on a large number of different cellular and molecular mechanisms. These include the formation of midline glial populations, and the expression of specific molecules required to guide callosal axons as they cross the midline. An additional mechanism used by callosal axons from neurons in the neocortex is to grow within the pathway formed by pioneering axons derived from neurons in the cingulate cortex. Data in humans and in mice suggest the possibility that different mechanisms may regulate the development of the corpus callosum across its rostrocaudal and dorsoventral axes. The complex developmental processes required for formation of the corpus callosum may provide some insight into why such a large number of human congenital syndromes are associated with agenesis of this structure.

The corpus callosum is a large fiber tract that connects neurons in the right and left cerebral hemispheres. Agenesis of the corpus callosum (ACC) is associated with a large number of human syndromes but little is known about why ACC occurs. In most cases of ACC, callosal axons are able to grow toward the midline but are unable to cross it, continuing to grow into large swirls of axons known as Probst bundles. This phenotype suggests that in some cases ACC may be due to defects in axonal guidance at the midline. General guidance mechanisms that influence the development of axons include chemoattraction and chemorepulsion, presented by either membrane-bound or diffusible molecules. These molecules are not only expressed by the final target but by intermediate targets along the pathway, and by pioneering axons that act as guides for later arriving axons. Midline glial populations are important intermediate targets for commissural axons in the spinal cord and brain, including the corpus callosum. The role of midline glial populations and pioneering axons in the formation of the corpus callosum are discussed. Finally the differential guidance of the ipsilaterally projecting perforating pathway and the contralaterally projecting corpus callosum is addressed. Development of the corpus callosum involves the coordination of a number of different guidance mechanisms and the probable involvement of a large number of molecules.