Loss Of The Er Membrane Protein Complex Subunit Emc3 Leads To Retinal Bipolar Cell Degeneration In Aged Mice

The endoplasmic reticulum (ER) membrane protein complex (EMC) is a conserved protein complex involved in inserting the transmembrane domain of membrane proteins into membranes in the ER. EMC3 is an essential component of EMC and is important for rhodopsin synthesis in photoreceptor cells. However, the in vivo function ofEmc3in bipolar cells (BCs) has not been determined. To explore the role ofEmc3in BCs, we generated a BC-specificEmc3knockout mouse model (namedEmc3cKO) using the Purkinje cell protein 2 (Pcp2) Cre line. Although normal electroretinography (ERG) b-waves were observed inEmc3cKO mice at 6 months of age,Emc3cKO mice exhibited reduced b-wave amplitudes at 12 months of age, as determined by scotopic and photopic ERG, and progressive death of BCs, whereas the ERG a-wave amplitudes were preserved. PKCa staining of retinal cryosections fromEmc3cKO mice revealed death of rod BCs. Loss ofEmc3led to the presence of the synaptic protein mGLuR6 in the outer nuclear layer (ONL). Immunostaining analysis of presynaptic protein postsynaptic density protein 95 (PSD95) revealed rod terminals retracted to the ONL inEmc3cKO mice at 12 months of age. In addition, deletion ofEmc3resulted in elevated glial fibrillary acidic protein, indicating reactive gliosis in the retina. Our data demonstrate that loss ofEmc3in BCs leads to decreased ERG response, increased astrogliosis and disruption of the retinal inner nuclear layer in mice of 12 months of age. Taken together, our studies indicate thatEmc3is not required for the development of BCs but is important for long-term survival of BCs.