Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

Indiana University-Purdue University Indianapolis (IUPUI) / Ciliopathies with multiorgan pathology include renal cysts and eye pathology. Previous studies showed meckelin (MKS3 protein product) are crucial to cilia function and its absence in Wpk rats (with mutated rMks3 gene) causes Leber's congenital amaurosis. Retinal photoreceptors have connecting cilium that joins the inner to the outer segment and plays a role in the transport of molecules necessary for morphological and molecular development and maintenance of the outer segment process. The present study evaluated meckelin expression during normal postnatal retinal development and the consequences of mutant meckelin on photoreceptor development and survival in Wistar-Wpk/Wpk rat. Meckelin was co-expressed in photoreceptors, amacrine, Muller glia and ganglion cells in postnatal day 10 (P10) and P21 wild type retinae. Meckelin was detected in both inner and outer segments of photoreceptors. By P10, both wild type and homozygous Wpk mutant retina had all retinal cell types. In contrast, by P21, cells expressing photoreceptor-specific markers in the Wpk mutant were fewer in number with abnormal expression patterns. Cell death assays confirmed a significant amount of cells undergoing apoptosis in the outer nuclear layer of the mutant rat retina. By electron microscopy, mutant photoreceptors did not develop an outer segment process beyond a connecting cilium and rudimentary outer segment. We conclude that MKS3 is not important for formation of connecting cilium and rudimentary outer segments, but is critical for the elongation and/or maintenance of mature outer segment processes.