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A precise knowledge of the timing and origin of the first cortical axons to project through the corpus callosum (CC) and of the subsequent emergence of callosal projection cells is essential for understanding the early ontogeny of this commissure. By using a series of mouse embryos and fetuses of the hybrid cross B6D2F2/J weighing from 0.36 g to 1.0 g (embryonic day E15.75-E17.25), we examined the spatial and temporal distribution of callosal projection cells by inserting crystals of the lipophilic dye (DiI: 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate) into the contralateral white matter just lateral to the midsagittal plane. Around 0.4 g or E15.8, retrogradely labeled cells were found restricted to a discrete cluster continuously distributed from the most ventral part of presumptive cingulate cortex to the hippocampus. During subsequent development, however, the tangential distribution of these labeled cells in ventromedial cortex did not extend further dorsally, and in fetuses where the CC became distinct from the hippocampal commissure (HC), labeled axons of cells in the ventral cingulate cortex were observed to intersect the callosal pathway and merge with labeled axons of the HC derived from cells in the hippocampus. The first cortical axons through the CC crossed the midline at about 0.64 g or E16.4, and these axons originated from a scattered neuronal population in the dorsal to lateral part of the presumptive frontal cortex. The earliest callosal cells were consistently located in the cortical plate and showed an immature bipolar appearance, displaying an ovoid- or pearl-shaped perikaryon with an apical dendrite coursing in a zig-zagging manner toward the pial surface and a slender axon directed toward the underlying white matter. Callosal projection cells spread progressively with development across the tangential extent of the cerebral cortex in both lateral-to-medial and rostral-to-caudal directions. In any cortical region, the first labeled cells appeared in the cortical plate and their number in the subplate was insignificant compared to that in the cortical plate. Thus, these results clarify that the CC is pioneered by frontal cortical plate cells, and the subsequent ontogeny of callosal projection cells proceeds according to the gradient of cortical maturation.

Hereditary absence of the corpus callosum (CC) provides an ideal experiment of nature for exploring mechanisms of axon guidance. In this study the prenatal development of CC axons in the acallosal mouse strains BALB/cWah1 and 129/ReJ or J was compared with normal hybrid mice by using the lipophilic dyes DiI and DiA. A few I/LnJ mice were also examined. The time of emergence and growth rate of CC axons from four cortical regions (frontal, parietal, temporal, occipital) were normal in acallosal strains. Their CC axons arrived at midplane on schedule but then often looped back to form the longitudinal Probst bundle. The frequency of formation of the Probst bundle was highest for axons from frontal cortex, which arrived at midplane first, and lowest for occipital axons, which arrived last. Once a few CC axons found a path to the other side via the hippocampal commissure, those that arrived later then crossed relatively normally. Some axons from the Probst bundle also managed to traverse midline in this manner. When no CC axons crossed, almost all of them entered the Probst bundle and eventually left it within a few hours to proceed in the ipsilateral white matter, never turning back toward midplane. Growth cones approaching midplane ipsilaterally and those that had crossed midline and entered contralateral white matter, as well as CC axons in the Probst bundle, expressed a normal range of size and complexity. These results demonstrate that the problem with callosal agenesis resides not in the cells of origin or the axons or growth cones themselves but in the substrates of axon guidance at the midsagittal plane.