*6.2. STK38L*

An early retinal degeneration was described in Norwegian Elkhounds in 1987 [136] in which the dogs present with vision impairment in low light as early as 6 weeks of age. The causal mutation was found to be a short interspersed element (SINE) insertion in exon 4 of *Stk38l*, a gene that had not been associated with retinal degenerations before its discovery in the Norwegian Elkhounds [137]. The mRNA transcript is produced in the affected dog but does not contain exon 4. Interestingly, at ~6 weeks of age, the expression of the mutant *Stk38l* transcript is similar to control dogs, but expression increases at ~8 and ~12 weeks [138].

Detailed histological experiments were performed on affected canine retina to understand the role of Stk38l in retinal development and how the lack of the functional protein results in retinal degeneration. The retina in ~4 week old *Stk38l*-affected dogs is normal, but by ~8 weeks of age the rod photoreceptors begin to show mislocalization of Rho, irregularities in the outer segments and increased TUNEL labeling. However, this increase in apoptotic cells is not accompanied by a thinning of the outer nuclear layer (ONL), as would be expected from loss of rod photoreceptors. The maintenance of ONL thickness is a result of proliferation of rod-like photoreceptors which express both Rho and cone S-opsin. After ~14 weeks of age, this proliferation ceases and the ONL begins to thin as the photoreceptors die, resulting in the loss of at least 50% of the ONL rows by 48 weeks [138].

The *Stk38l*-affected dogs provide an interesting and unique model of retinal degeneration in which differentiated photoreceptors either apoptose or proliferate for a short amount of time before retinal degeneration progresses.

### **7. Photoreceptor to Bipolar Cell Signaling**
