Axon Guidance In The Mouse Olfactory System
Within the mouse olfactory system, 1200 different types of olfactory sensory neurons use molecular cues to appropriately target stereotyped locations within the olfactory bulb. Recent studies reveal that some of these molecular cues are regulated by olfactory receptor mediated neuronal activity. Within this thesis we develop a hypothesis drive microarray based method to identify novel axon guidance molecules expressed by the target of this process, the olfactory bulb. This method is designed to identify genes that are differentially expressed within the developing olfactory bulb during the developmental stages when olfactory sensory neurons are first reaching and converging within the olfactory bulb. We identify an entire gene family, the δ protocadherins, which fulfill these characteristics and are expressed within subsets of olfactory sensory neurons in the olfactory epithelium. Furthermore, we find that many of the δ protocadherins are regulated by neuronal activity within the olfactory system and hippocampus. Biochemical analysis of the δ protocadherins reveals novel heterophilic interactions between the extracellular domains of some family members, as well as heterophilic interactions between Pcdh10 and some classical cadherins. Furthermore, we identify the ability of the cytoplasmic domains of these proteins to translocate to the nucleus. Ectopic expression through transgenic analysis of one family member, Pcdh10, is sufficient to disrupt proper axon targeting of SR1 olfactory neurons. Based on this data we propose that the δ protocadherins are excellent axon guidance candidate molecules in the mouse olfactory system.
Dissertation or Thesis