Transcriptional Regulation Of The Nuclear Development Of The Trigeminal Nerve In The Brain And The Molecular Mechanisms Of Axon Guidance Of The Medial Lemniscus

The mesencephalic trigeminal nucleus (Me5) innervates muscle spindles and is responsible for receiving and transmitting proprioception from the oro-facial region. Molecular mechanisms underlying the development of the Me5 are poorly understood. Evidence is provided here that transcription factor Drg11 is required for Me5 development. Drg11 was expressed in the Me5 cells of the embryonic and early postnatal mouse brains, and the Me5 cells were absent in Drg11-/- mice at birth. The absence of the Me5 cells in Drg11-/- mice appeared to be caused by increased cell death in the Me5 during embryonic development. In postnatal Drg11-/- mice, Me5 cell innervation of masseter muscle spindles was undetectable, while robust trigeminal motoneuron innervation of masseter muscle fibers was detected. The postnatal body weight of Drg11-/- mice was notably less than that of wild-type mice, and this might result, in part, from disruption of the oro-facial proprioceptive afferent pathway. Taken together, our results demonstrate an essential role for Drg11 in the development of the Me5. The dorsal column-medial lemniscal system is a significant sensory pathway mediating the sensation of touch and limb position. In this system, axons from the second-order neurons in dorsal column nuclei (DCN) form internal arcuate fibers, cross medulla midline, and then project rostrally to the thalamus. Here we demonstrate that DCC (deleted in colorectal cancer), which is expressed in the developing DCN, is indispensable for the establishment of medial lemniscal system. Axons from the DCN cross the midline at around embryonic day 11 in mice. At this stage, Netrin-1 and its receptor DCC are expressed in the floor plate and commissural fibers there, respectively. Our neural tracing experiments showed that some axons from the DCN arrived near the floor plate in DCC-/- mice, but these fibers were much less fasciculate and failed to cross the midline. Surprisingly, they projected ipsilaterally to the ventrolateral thalamus. DCCkanga is a spontaneous mutant lacking intracellular P3 domain of DCC. In DCCkanga-/- mice, axons from DCN were fasciculate and grew toward the floor plate, similar to that of the wild-type. However, some of these DCCkanga-/- fibers crossed the midline, forming medial lemniscal decussation, while others did not and remained on the ipsilateral side. Strikingly, both midline-crossing and uncrossing DCN axons projected rostrally to the posterior ventrolateral thalamus. On the other hand, gross development of DCN axons exhibited normal in unc5h3 (another Netrin-1 receptor) mutant mice. Taken together, our results demonstrate an essential role of DCC in the establishment of dorsal column-medial lemniscal system.