Hajime Fujisawa

Hippocampal mossy fibers project preferentially to the proximal-most lamina of the suprapyramidal region of CA3, the stratum lucidum, and proximal-most parts of the infrapyrmidal region of CA3c. Molecular mechanisms that govern the lamina-restricted projection of mossy fibers, however, have not been fully understood. We previously studied functions of neural repellent Semaphorin-6A (Sema6A), a class 6 transmembrane semaphorin, and its receptors, plexin-A2 (PlxnA2) and PlxnA4, in mossy fiber projection and have proposed that PlxnA4-expressing mossy fibers are principally prevented from entering the Sema6A-expressing suprapyramidal and infrapyramidal regions of CA3 but are permitted to grow into proximal parts of the regions, where repulsive activity of Sema6A is competitively suppressed by PlxnA2 (Suto et al., 2007). In the present study we demonstrate that Sema6B, another class 6 transmembrane semaphorin, is expressed in CA3 and repels mossy fibers in a PlxnA4-dependent mannerin vitro. InSema6B-deficient mice several mossy fibers aberrantly project to the stratum radiatum and the stratum oriens. The number of aberrant mossy fibers is increased inSema6A;Sema6Bdouble knock-out mice, indicating that Sema6A and Sema6B function additively to regulate proper projection of mossy fibers. PlxnA2 does not suppress the Sema6B response, but itself promotes growth of mossy fibers. Based on these results, we propose that the balance between mossy fiber repulsion by Sema6A and Sema6B and attraction by PlxnA2 and unknown molecule(s) prescribes the areas permissive for mossy fibers to innervate.

Background: The trajectory of corticospinal tract (CST) axons from cortex to spinal cord involves a succession of choice points, each of which is controlled by multiple guidance molecules. To assess the involvement of transmembrane semaphorins and their plexin receptors in the guidance of CST axons, we have examined this tract in mutants of Semaphorin-6A (Sema6A), Plexin-A2 (PlxnA2) and Plexin-A4 (PlxnA4). Results: We describe defects in CST guidance in Sema6A mutants at choice points at the mid-hindbrain boundary (MHB) and in navigation through the pons that dramatically affect how many axons arrive to the hindbrain and spinal cord and result in hypoplasia of the CST. We also observe defects in guidance within the hindbrain where a proportion of axons aberrantly adopt a ventrolateral position and fail to decussate. This function in the hindbrain seems to be mediated by the known Sema6A receptor PlxnA4, which is expressed by CST axons. Guidance at the MHB, however, appears independent of this and of the other known receptor, PlxnA2, and may depend instead on Sema6A expression on CST axons themselves at embryonic stages. Conclusion: These data identify Sema6A as a major contributor to the guidance of CST axons at multiple choice points. They highlight the active control of guidance at the MHB and also implicate the inferior olive as an important structure in the guidance of CST axons within the hindbrain. They also suggest that Sema6A, which is strongly expressed by oligodendrocytes, may affect CST regeneration in adults.