Deletion of the transmembrane protein Prom1b in zebrafish disrupts outer-segment morphogenesis and causes photoreceptor degeneration

Abstract

Edited by Xiao-Fan Wang Mutations in human prominin 1 (PROM1), encoding a transmembrane glycoprotein localized mainly to plasma membrane protrusions, have been reported to cause retinitis pigmentosa, macular degeneration, and cone-rod dystrophy. Although the structural role of PROM1 in outer-segment (OS) morphogenesis has been demonstrated in Prom1-knockout mouse, the mechanisms underlying these complex disease phenotypes remain unclear. Here, we utilized a zebrafish model to further investigate PROM1's role in the retina. The Prom1 orthologs in zebrafish include prom1a and prom1b, and our results showed that prom1b, rather than prom1a, plays an important role in zebrafish photoreceptors. Loss of prom1b disrupted OS morphogenesis, with rods and cones exhibiting differences in impairment: cones degenerated at an early age, whereas rods remained viable but with an abnormal OS, even at 9 months postfertilization. Immunofluorescence experiments with WT zebrafish revealed that Prph2, an ortholog of the human transmembrane protein peripherin 2 and also associated with OS formation, is localized to the edge of OS and is more highly expressed in the cone OS than in the rod OS. Moreover, we found that Prom1b deletion causes mislocalization of Prph2 and disrupts its oligomerization. We conclude that the variation in Prph2 levels between cones and rods was one of the reasons for the different PROM1 mutation-induced phenotypes of these retinal structures. These findings expand our understanding of the phenotypes caused by PROM1 mutations and provide critical insights into its function.

Zebrafish Models of Photoreceptor Dysfunction and Degeneration

“…PROM1 plays a critical role in outer segment disc morphogenesis and PROM1 mutations cause a variety of photoreceptor diseases, such as RP, CORD, and macular degeneration [ 227 , 228 , 229 ]. Zebrafish with prom1b mutations have a cone degeneration, starting with red and green cones and affecting blue and UV cones soon after [ 230 ] ( Table 7 ; see for list of zebrafish mutant models of cone dystrophy). While rods do not appear to degenerate in prom1b mutants, they have overgrown OSs.…”

Childhood-onset genetic cone-rod photoreceptor diseases and underlying pathobiology

“…Murine studies indicate that Prom1 mutations cause disruption of photoreceptor disk morphogenesis and mislocalisation of visual pigments that interfere with phototransduction and result in photoreceptor degeneration [38 , 39] . Zebrafish studies suggest that cones may be more severely affected than rods since mutations in Prom1 affected peripherin 2 (Prph2) localization and oligomerization, and Prph2 is expressed at higher levels in cones [40] . The majority of reported mutations in PROM1 cause autosomal recessive disease, but specific variants (p.Arg373Cys, p.Asp829Asn and p.Leu245Pro) cause dominant disease.…”

Electrophysiological and Pupillometric Abnormalities in PROM1 Cone–Rod Dystrophy

“…Prominin-1 is a transmembrane glycoprotein that localizes to the base of photoreceptor outer segments and is thought to be involved in disc assembly and maintenance of outer segment structure. 1,2 These dystrophies can be inherited in autosomal dominant (AD) or autosomal recessive (AR) forms. AD PROM1 dystrophy tends to have a later onset and a milder phenotype compared to AR PROM1 dystrophy.…”