Using the chicken embryo as an experimental model, we have shown that corridor-like cells share all the intrinsic characteristics of their mouse homologs (Lopez-Bendito et al., 2006), including a remarkably similar capacity to guide TAs, but these neurons converge toward the midline and, hence, are never in contact with TAs in vivo. Thus, the specification and overall migration of corridor-like cells seem independent of their role in TA guidance, thereby suggesting that these neurons may exert other ancestral functions and that their

guidepost function for TAs has been acquired secondarily. Most importantly, our observations indicate that a cardinal difference between living reptiles and mammals lays in the orientation of migration of neurons that have the cellular capacity to guide TAs. Furthermore, using find more Slit2−/− mutant mice, we showed that the proper positioning of corridor cells by migration is required and sufficient to switch TAs from an external default path to a mammalian internal route ( Figure 8H). Thus, the corridor acts in mice as an anatomical “hotspot” in which local changes in cell migration have long-range and large-scale effects on the guidance of TAs. Taken together, our experiments strongly support a surprising evolutionary scenario in which changes in the

migration of intermediate neurons have provided an opportunity for the opening of a major axonal highway. To unravel the molecular mechanisms GW3965 cost underlying the evolutionary change in corridor neuron migration, we focused on the secreted factor Slit2. In this study we showed that (1) Slit2 is differently expressed in the vMGE&POA of mouse and chicken embryos; (2) Slit2 acts as a short-range repellent on the Pentifylline migration of corridor cells; (3) modifying Slit2 levels in the ventral telencephalon of chicken embryos distorts the shape of the corridor; and (4) Slit2 inactivation impairs the mammalian-specific

migration of corridor neurons by shifting them toward the midline, a behavior reminiscent of chicken corridor-like cells. These results reveal that Slit2 is a major determinant in the orientation of mouse corridor neuron migration, by acting at short-range from the vMGE&POA, and thereby controls TA trajectory. Thus, in contrast to a direct role of Slit2 on axonal navigation ( Bagri et al., 2002, Braisted et al., 2009, Nguyen-Ba-Charvet et al., 2002 and Shu et al., 2003b), our study provides a different mechanism of Slit function on longitudinal axonal positioning through a short-range activity in guidepost cell migration. This relay of midline signaling by an early and, thus, local activity in intermediate target cells may more generally explain how midline cues can act at long range in very large structures, such as the mammalian telencephalon.