OLIGOPHRENIN-1, A RHO-GAP PROTEIN INVOLVED IN CENTRAL COGNITIVE FUNCTION, IS EXPRESSED IN SPECIFIC NEURONS OF THE ENTERIC NERVOUS SYSTEM

Junhua Xiao, Craig B. Neylon, John B. Furness, Department of Anatomy & Cell Biology and Centre for Neuroscience, University of Melbourne, Vic.

Oligophrenin-1 is one of seven genes found in which a mutation causes nonsyndromic mental retardation (MRX), an inherited disease affecting 1 in 600 males. MRX genes have been thought to affect only central neurons, and have provided dramatic insight into the underlying mechanisms of brain development, memory and learning. Oligophrenin-1 is a 802 amino acid protein that interacts directly with Rho-GTPase subfamily members to regulate dendritic shape, which plays a crucial role in neuronal network connectivity and synaptic transmission. As changes in the physiological properties of enteric neurons have been reported in the intestine after transection, in diseases of the human gastrointestinal tract, and in animal models of gastrointestinal pathology, identification of the molecules regulating connectivity of enteric neural networks may lead to better understanding of enteric neuron plasticity. We examined the expression and localization of the oligophrenin-1 gene in the enteric nervous system of the guinea pig. RT-PCR assays revealed expression of oligophrenin-1 mRNA in guinea pig ileum longitudinal muscle myenteric plexus. Sequencing of the PCR product revealed 90% identity with human oligophrenin-1 (accession NM_002547) and 87% with mouse oligophrenin-1 (accession NM_052976). Western blotting of purified ganglionic cell lysate revealed a 91 kDa protein (oligophrenin-1) and another immunoreactive protein of higher molecular weight (164 kDa). In immunohistochemistry, oligophrenin-1 was localized specifically to enteric neurons, and not glial cells, smooth muscle or other cell types. Double-labeling experiments indicated preferential expression in neurons with dendrites, ie; interneurons and motor neurons. About 78% and 82% of neurons were immunoreactive in the myenteric plexus (MP) and submucosal plexus (SMP), respectively. Oligophrenin-1 was found in the cytoplasm of neurons, but under some conditions could be translocated to the nucleus. These findings indicate that oligophrenin-1 may be an important molecule regulating neuronal connectivity in the enteric nervous system.