The generation of the central and peripheral nervous systems depends on the migration of neuroblasts to appropriate destinations. Migration has three major steps: initiation of movement from the generative zone, movement through tissue toward the final destination and the cessation of migration once this goal is reached. Intermediate delays prior to the final stopping can also be important for the final organization of the system in question. The gonadotropin release hormone (GnRH) neurons which regulate reproductive function can first be detected by the presence of the GnRH peptide or precursor mRNA in the nasal placode. From there they migrate along the olfactory (chick) or vomeronasal (mammals) nerves into the CNS. In doing so they cross the basal lamina of the olfactory epithelium, the extracellular matrix of the nerve and the basement membrane of the glia limitans. Our data clearly indicate that the serine protease, trypsin, and a nexin-like inhibitor modify the barrier function in these regions. Such modifications can, in a stage and site specific manner, alter accessibility of cells to their migratory route. We propose testing the hypothesis that alterations in matrix barriers will have long term affects on the final distribution of GnRH neurons. That the establishment of the regional sub-populations of GnRH neurons are based, in part, on the information present within their environments (epithelium, nerve, CNS) over developmental time. To test this hypothesis the protease or inhibitor are delivered via an Affigel Blue beard applied to the nasal place and brains analyzed for the GnRH cell location when the adult distribution has been reached (prior to hatch). Anatomical studies will examine both naturally occurring and experimentally induced alterations in the epithelial and glia limitans barriers. A second way in which position information can be codes is via descent from specific precursors. In the hindbrain a progenitor imparts information restricting movements of daughters to a limited zone. In the cortex and diencephalon, which are more complex, some daughter cells have restricted distributions while others migrate far from their siblings. Hence the descent from a common precursor can provide a range of information can provide a range of information to the final members of the clone as to their position with the CNS. To test the hypothesis that lineage, in combination with matrix modulation, plays a role in the """"""""organized chaos"""""""" that typifies the GnRH network we shall make use of a highly complex replication deficient retroviral library and single cell PCR analysis of infected GnRH neurons. The experiments are designed such that the role of lineages in the spatial organization of the GnRH network will be known.
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