Tulp1-flox Mouse

TULP1, or tubby-like protein 1, is a photoreceptor-specific protein. It is crucial for protein trafficking in photoreceptor cells, likely acting as an adapter molecule linking vesicles to molecular motors and the cytoskeletal scaffold. It is involved in the vesicular trafficking of several photoreceptor proteins from the inner segment to the outer segment, and is associated with maintaining the proper localization of proteins like PRCD to photoreceptor outer segment discs [2,3].

In zebrafish, knockout models have been generated. Knockout of tulp1a led to mislocalization of UV cone opsins and UV cone degeneration, while knockout of tulp1b caused mislocalization of rod opsins and rod-cone degeneration. The double knockout (tulp1-dKO) zebrafish had opsin mislocalization in all photoreceptor types and severe early-onset degeneration. In tulp1-dKO zebrafish, photoreceptor cilium length was reduced, and the expression of tektin2 (a ciliary and flagellar microtubule structural component) was downregulated, suggesting that Tulp1 may transcriptionally activate the tekt2 promoter. Also, ferroptosis might be activated in tulp1-dKO zebrafish, as indicated by up-regulation of ferroptosis-related genes, mitochondrial changes, and iron and lipid droplet deposition in the retina [1].

In conclusion, TULP1 is essential for normal photoreceptor function, especially in protein trafficking and ciliogenesis. The zebrafish knockout models have revealed that loss of TULP1 can lead to cilia structure defects, opsin trafficking problems, and ultimately photoreceptor death via ferroptosis. These findings contribute to understanding the pathogenesis of early-onset retinal degeneration, a disease associated with TULP1 mutations [1].