The role of MeCP2 in cell adhesion molecule expression regulation in the olfactory system

Olfaction plays a critical role in survival and reproduction in many animal species. Odorant molecules in the environment are sensed by olfactory sensory neurons (OSN) located in the nasal cavity. Whereas a given odorant receptor (OR) is expressed by neurons scattered in broad zones of the olfactory epithelium (OE), the axons from OSNs that express the same OR converge onto a defined glomerulus in the olfactory bulb (OB). This precise axonal connectivity provides an excellent model to study developmental mechanisms of neural network formation.The guiding mechanisms for OSN axon targeting and convergence remain to be identified. One current model for OSN axon convergence suggests that specific OR-expressing OSN subpopulations express corresponding combinations of cell adhesion molecules (CAMs). The combination of CAMs determines the final destination of OSN axon convergence. To test this hypothesis, it is important to identify all cell adhesion molecules expressed by OSNs and further explore the regulatory mechanisms of CAM differential expression among different subpopulation of OSNs.In this study, I characterized the dynamic and cell type-specific expression of a novel protocadherin (Pcdh), Pcdh20, in the olfactory system. Pcdh20 is specifically expressed in newly differentiated OSNs and their axons during development. Pcdh20 expression is down-regulated in the adult olfactory system, except in a small OSN population. These small, discrete numbers of Pcdh20-positive glomeruli in the adult OB are consistently clustered in the ventral-caudal region in both male and female mice. However, adult males have higher numbers of Pcdh20-positive glomeruli with a broader distribution, whereas adult females have fewer Pcdh20-positive glomeruli with a more restricted distribution.To investigate the regulatory mechanisms of CAM expression, I studied the regulatory effect of MeCP2 for selected cell adhesion molecule expression in the olfactory system. MeCP2 is a transcription regulator that binds specifically to methylated CpG dinucleotides in the promoter region. MeCP2 is widely expressed in all tissues, but is more abundant in the brain and also in the OE. Using olfactory receptor-specific traceable mice, M71-IRES-tauLacZ transgenic mice, I observed that MeCP2 is required for the convergence of OSN axons. Mecp2 deficiency results in an incomplete coalescence of OSN axons. The axonal phenotype in Mecp2 deficient mice may be the result of misregulation of cell adhesion molecules, Kirrel2 and Kirrel3, expression. Mecp2 not only regulates the expression levels of Kirrel2 and Kirrel3 but also determines the differential characteristics of these CAMs expressions among OSNs. In addition, using chromatin immunoprecipitation (ChIP), I demonstrated that MeCP2 directly binds to CpG islands in Kirrel2 and Kirrel3 promoter regions, and therefore likely to directly regulate their transcription. Mecp2 regulation of CAM expression is an activity dependent event. Odorant stimulation induces phosphorylation of MeCP2 at Serine80 and results in changes in CAMs expression.These data together suggest that CAM expression is dynamically regulated in the OSNs. Transcription factor and neuronal activity are critical players for this regulation. Our data so far supports the neuronal identity model. Further identification of differential CAM expression and its regulation will provide insight into how precise neural networks are established during development.