Study On The Function Of Dlicl Gene In Mouse Retinitis Pigmentosa

Retinitis pigmentosa is an inherited blinding disease characterized by photoreceptors cell death. Over fifty genes responsible for this genetic disease have been identified, but no effective treatment is available in the clinic. It is important to know the pathogenesis of this disease at cellular and molecular level.Dynein is a motor protein that transport toward the minus end of microtubules and plays important roles in cellular protein transport and cellular organelle position. Mammalian Dlic1encodes the dynein light intermediate chain1, a subunit of dynein complex. We studied the function of Dlic1in mice by developing the Dlic1gene knockout mice. We found that the Dlic1-1-mouse was viable, but the photoreceptors developed abnormally and then died gradually via apoptosis. We further studied the function of Dlic1in photoreceptors and the molecular mechanism of photoreceptor degeneration. We found that the proteins destined to outer segments were accumulated in the cell body after synthesis by immunofluorescence staining. In Dlic1-/-photoreceptors the protein transport from ER to Golgi is blocked, which leads to the dilated ER lumen, but the dilated ER lumen does not activate UPR response. Deletion of Dlid1led to the accumulation of Rabll vesicles around nuclei, indicating the blockage of transport from Golgi to cilium. Our studies also revealed that Dlic1deficiency impaired ciliogenesis in both photoreceptors and MEF cells.Further mechanistic studies revealed that the distribution of both dynein heavy chain (DHC) and intermediate chain (DIC) were dramatically decreased in the inner segment of Dlic1-/-photoreceptors. Furthermore, deletion of Dlic1led to destabilization of DHC and DIC, resulting in a reduction of dynein at protein level. Altogether they impaired the total transport ability of dynein in cytosol.Based on the results above we postpone that Dlic1deficiency-mediated decrease of the protein levels and abnormal distribution of dynein in photoreceptors impaired the transport function of dynein and normal cilium development, ultimately resulting in the accumulation of proteins in the cell body and then leads to death of the photoreceptor via apoptosis. Therefore, the Dlic1-/-mice provide a new animal model for studying mechanisms underlying retinitis pigmentosa in humans.