Regulation of gene expression in the olfactory neuroepithelium: a neurogenetic matrix

The olfactory neuroepithelium exhibits neurogenesis throughout adult life, and in response to lesions, a phenomenon that distinguishes this neural tissue from the rest of the mammalian brain. The newly formed primary olfactory neurons elaborate axons into the olfactory bulb. Thus, denervation and subsequent reinnervation of olfactory bulb neurons may occur throughout life. This unique ability of the olfactory neuroepithelium to generate new neurons from a population of precursor cells present in the basal cell layer of this tissue makes it a valuable model in the study of neural development and regeneration. The molecular processes underlying the neurogenic properties of the olfactory neuroepithelium are poorly understood. Here we have reviewed our studies on the expression of B50/GAP43 during ontogeny of the olfactory system and following lesioning. This analysis includes the characterization of the expression of OMP, a protein expressed in mature olfactory neurons, as well as PKC and calmodulin. The latter two molecules are of particular interest to the function of B50/GAP43 since the degree of phosphorylation of B50/GAP43 appears to determine B50/GAP43's ability to bind calmodulin (see also Storm, chapter 4, this volume). In the mature olfactory epithelium B50/GAP43 expression is restricted to a subset of cells located in the basal region. Since the expression of B50/GAP43 is high in developing and regenerating nerve cells we are confident that the B50/GAP43 positive cells are new neurons derived from the stem cells in the basal region of the epithelium. B50/GAP43 is absent from the stem cells themselves and also from the mature OMP-expressing neurons. On the basis of the patterns of B50/GAP43 and OMP expression two stages could be discriminated in the regeneration of the olfactory epithelium. First, as an immediate response to lesioning a large population of B50/GAP43 positive, OMP negative neurons are formed. Subsequently, during the second stage, these newly formed differentiating neurons mature as evidenced by a decrease in B50/GAP43 and an increase in OMP expression. The second stage in the regeneration process is only manifested if the regenerating neurons can reach their target cells in the olfactory bulb. Hence, bulbectomy results in the arrest of the reconstituted olfactory epithelium in an immature state. The differential patterns of B50/GAP43 expression following peripheral lesioning and bulbectomy suggest the existence of a target derived signal molecule involved in the down-regulation of B50/GAP43 expression in olfactory neurons that have established synaptic contacts in the olfactory bulb (see also Willard, chapter 2, this volume, "the suppressor hypothesis").(ABSTRACT TRUNCATED AT 400 WORDS)