Cdhr1a and pcdh15b may link photoreceptor outer segments with calyceal processes revealing a potential mechanism for cone-rod dystrophy

Inherited retinal diseases (IRDs) are a group of disorders that can severely affect vision and even lead to blindness affecting over 450,000 individuals in the US alone (Ackland et al., 2017). Cone-rod dystrophy (CRD) is a subset of IRD that leads to cone photoreceptor cell (PRC) degeneration followed by decline of rod PRCs (Ackland et al., 2017; Bowne and Diager, 2020). The disorder generally stems from mutations in one of the over 30 gene candidates. Function of a putative CRD candidate, CDHR1 has been known to clinically correlate with recessive CRD (Arno et al., 2016; Duncan et al., 2012; Stingl et al., 2017). CDHR1, a photoreceptor-specific cadherin, was first investigated by Rattner and colleagues in 2001 (previously PCDH21) where it was shown that a mouse KO resulted in early onset retinal degeneration, at 1 month and severe degeneration by six (Rattner et al., 2001). Subsequent studies have shown that initial retinal degeneration involves loss of cones and subsequently rods (Yusuf et al., 2021). Molecularly, in the mouse model, it’s been shown that CDHR1 localizes at the leading edge of OS discs and forms cadherin-based junctions to an unknown partner in the inner segment (Rattner et al., 2001; Burgoyne et al., 2015). These connections have been hypothesized to regulate nascent rod OS disc release into the mature OS (Rattner et al., 2004). However, CDHR1 function in cones has not been postulated. In Xenopus, absence of Cdhr1 results in overgrown OS discs at the basal OS, thereby disrupting the normal OS (Carr et al., 2021). In humans, CDHR1 mutations, both truncations and missense mutations, have been shown to correlate with late onset CRD (Stingl et al., 2017; Ba-Abbad et al., 2021; Bolz et al., 2005; Ostergaard et al., 2010). Clinically, these studies identify various pathogenic variants and variants of unknown significance; however, the exact mechanism behind CDHR1-based CRD pathogenesis remains unknown.

CDHR1, like other cadherins, encodes an intracellular domain, a transmembrane domain, and six evolutionarily conserved extracellular cadherin domain repeats (EC repeats; Rattner et al., 2001; Rattner et al., 2004). The cytoplasmic domains of classical cadherins have been shown to bind beta-catenin, which anchors the cadherin to various cytoskeletal elements such as actin (Aberle et al., 1996). Interestingly, the cytoplasmic domain of Cdhr1 diverges considerably from other cadherins and is predicted to not possess any beta catenin or cytoskeletal binding activity (Rattner et al., 2004; Yang et al., 2008). ECs of most cadherins possess negatively charged sequence motifs, which are involved in Ca²⁺ binding (Hirano et al., 1987). These ECs form either homophilic or heterophilic junctions in trans conformation and thereby mediate inter/intracellular connections (Takeichi et al., 1986). Protocadherins generally consist of six to seven EC repeats and are predominantly observed with high diversity in various neuronal populations (Pancho et al., 2020). In neurons, protocadherins are responsible for synaptogenesis, neuronal specificity, and formation of mechanical junctions (Halbleib and Nelson, 2006). Based on mouse studies, CDHR1 forms connections with the IS to what appears to be the periciliary ridge and an extension of the IS appearing to be the calyceal process (Burgoyne et al., 2015).

Calyceal processes (CPs) were first described by Cohen, 1961 (as calyx of a flower) surrounding the basal OS discs in rhesus macaque and pigeon photoreceptors (Cohen, 1961). Pioneering work in the 1970–80 s showed these processes are actin-based microvilli projections of the IS found in both rods and cones of various vertebrates including zebrafish and humans (Burnside, 1978; Chaitin and Bok, 1986). In macaque PRCs, thicker, longer, and more numerous CPs were observed surrounding cones versus rods (Sahly et al., 2012). Based on their proximity to the OS, CPs were hypothesized to structurally support the OS discs in both rods and cones (Sharkova et al., 2024). However, functional evidence of their potential aid to the OS remains scarce. Previous studies also show how CPs are absent and a vestigial remanence of periciliary ridge extension is observed in popular rodent models such as mice and rats, which may suggest a lack of functional evidence of CPs (Sahly et al., 2012; Cohen, 1960). Studies in macaque PRCs indicated localization of various Usher syndrome 1 (Ush1) proteins to the calyceal processes (Sahly et al., 2012). Clinically, Usher syndrome 1 is categorized by loss of hearing and vision due to mutations in one of the six Ush1 genes (Mathur and Yang, 2015). Of these six Ush1 genes, Pcdh15 has been shown to make heterophilic cadherin-based junctions in stereocilia of hair cells with another Ush1 gene, Cadherin 23 (Cdh23; Kazmierczak et al., 2007). Thereby, they form a mechanical bridge between adjacent stereocilia. Mechanical deflection of stereocilia due to sound waves changes the tension of Pcdh15-Cdh23 based interactions, which then triggers the mechano-electrical transduction channel for signal propagation (Goldberg, 2006; McPherson, 2018). Loss of functional Pcdh15 results in Usher syndrome type 1 f, entailing the loss of hearing and vision (Lelli et al., 2010). In PRCs, Pcdh15 has been unequivocally shown to be localized in the CPs (Sahly et al., 2012; Miles et al., 2021; Schietroma et al., 2017). Interestingly, loss of pcdh15b function in zebrafish results in an abnormal OS phenotype and PRC degeneration (Miles et al., 2021). However, the mechanism of pcdh15b-based PRC pathogenesis remains unknown. Noting the expression of two retinal cadherins in juxtaposing structures, CDHR1 in the OS and PCDH15 in the CP, we sought out to investigate whether CDHR1 and PCDH15 interact to link the OS discs and the CP.

In our current study, we demonstrate that in zebrafish PRCs, cdhr1a and pcdh15b juxtapose along the OS and CP, suggesting they form functional connections. Importantly, we show that this localization pattern is evolutionarily conserved up to and including humans. Furthermore, we confirm pcdh15b-cdhr1a interactions via immunoprecipitation and K562 cell aggregation. While modeling CRD using a cdhr1a loss-of-function mutant line, we report progressive defects in CP morphology correlating specifically with cone degeneration. Taken together, we propose that loss of cdhr1a function disrupts OS-CP junctions and subsequently leads to CRD.

Discovered over 20 years ago, the retinal cadherin CDHR1 is clinically associated with recessive CRD, yet its exact molecular function continues to remain a mystery. In our current study, we found that the zebrafish homologue of CDHR1, cdhr1a, localizes to cone and rod OSs in a pattern mirroring that of the inner segment CP and its own resident cadherin pcdh15b (PCDH15 homolog in zebrafish) (Figure 1). Interestingly, the pattern of CDHR1/PCDH15 localization was observed across various species, including amphibians, rodents, birds, primates, and humans, thus indicating a high degree of mechanistic evolutionary conservation (Figure 2). Aquatic species, zebrafish, and xenopus, appear to have retained significant length of their cone CPs, particularly along the UV cones, as evident by the length of cdhr1/pcdh15 signal (Figure 1C and E). Conversely, in rodents, which have been previously shown to either lack CPs or contain a single vestigial structure, CDHR1/PCDH15 juxtaposition is still maintained, albeit in a very short segment (Sahly et al., 2012). Intriguingly, the size of the CP may be related to the diurnal nature of an organism as the gerbil exhibited longer structures compared to rats and mice (Figure 2H). Birds and primates exhibit CP lengths longer than rodents but still shorter than fish or frogs (Figure 1K–L). In addition to localization, we showed that cdhr1a physically interacts with pcdh15b in vitro, via co-immunoprecipitation and in vivo via the K562 cell aggregation assay (Figure 3). Furthermore, using immuno-gold TEM, we observed direct interaction between cdhr1a and pcdh15b at the photoreceptor-CP interphase region. Taken together, the localization and interaction findings provide the first potential clue to the molecular function of CDHR1 and the etiology of CDHR1-associated CRD. Based on these findings, we therefore hypothesized that cdhr1a links the OSs with the CPs via interactions with pcdh15b and postulate the absence of this interaction as a mechanism driving cone cell degeneration.

To test our hypothesis, we tracked CRD progression in zebrafish using single cdhr1a^-/- or pcdh15b^-/- mutant lines as well as a cdhr1a^-/-, pcdh15b^-/- double mutants. Taking advantage of the zebrafish system, we were able to examine CRD progression at numerous developmental and adult stages at the molecular level with high resolution. When examining the cdhr1a^-/- model, we documented progressive disorganization and shortening of cone OS starting at 30 dpf, while observing only minor effects in rods (Figures 5 and 6). Interestingly, disorganization and shortening of cone OSs at 30 dpf was preceded by slight but significant lengthening at 5 and 10 dpf. This suggests that early development of the OS may be regulated by CP-OS interactions to ensure proper rate of OS growth (Figure 5H). Cdhr1a^-/- cones exhibited shortened and disorganized CPs as early as 5 dpf, indicating that defects in CP-OS interactions precede and may therefore lead to cone OS instability (Figure 7). However, we also observed mutant CP overgrowth at 15 dpf, suggesting that CP assembly or maintenance is misregulated in the absence of cdhr1a (Figure 7O). A striking phenotype observed in mutant cone OSs was the misorganization of prph2 signal. Normally, prph2 signal appears smoothly along the periphery of cone OS and largely absent from the center; however, in cdhr1a^-/- cones, we observe an almost disc-like horizontal staining of prph2 throughout the OS as early as 15 dpf and very clearly by 30 dpf (Figure 5B’–G’). Prph2 misorganization was also accompanied by the appearance of cone OS bending and tilting, compared to wildtype (Figure 5A–G’). Similar prph2 localization phenotypes have been observed in prom1b mutant zebrafish, which is interesting as prom1 has been shown to interact with Cdhr1 (Yang et al., 2008). Perhaps loss of prom1b results in the mis-localization or mis-regulation of cdhr1a in the cone OS and therefore also compromises CP-OS interactions leading to similar phenotypes. Finally, using TEM, we observed that cdhr1a^-/- cone OSs displayed disorganized disc stacking, which supports the observed prph2 localization phenotype (Figure 5K and L). Compared to previous studies of cdhr1 function in frogs or pcdh15b function in zebrafish, we did not observe disc overgrowth in 15 dpf zebrafish. This may result from disorganization and loss of OS integrity already by 15 dpf. Disc overgrowth may therefore be observed at earlier timepoints but those were not examined in our studies. Several previous studies have postulated that CP-OS interactions are critical for stability of cone OSs (Sahly et al., 2012; Sharkova et al., 2024; Schietroma et al., 2017). Our data supports this notion where cdhr1a mutant cone OSs are shorter and often appear tilted to one side. Similar OS phenotype results were also observed in pcdh15b mutants up to 10 dpf which is in line with previous reports from zebrafish and what was also observed in xenopus embryos injected with Pcdh15 morpholinos (Miles et al., 2021; Schietroma et al., 2017). Surprisingly, pcdh15b heterozygotes exhibited slight but significant reduction in cone OS and CP length (Figure 8E and H). This suggests that steady-state levels of pcdh15b protein are critical for its function. Pcdh15b mutants display cone OS defects earlier than cdhr1a^-/- and do not exhibit the early increase in OS length (Figure 8). This might suggest that the absence of pcdh15b interferes with CP function, while the absence of cdhr1a interferes with OS-CP connections but not the CP itself. In humans, PCDH15 mutations are associated with rod-cone dystrophy; however, due to the lethality of the pcdh15b mutation by 15 dpf, we are not able to compare long-term pcdh15b mutant phenotypes with cdhr1a mutants. In the double mutants, due to the absence of both cadherins, we observed shorter and disorganized CPs and cone OSs as early as 5 dpf, normally not seen in either single mutant alone (Figure 9). By 10 dpf, the double mutant phenotypes were severe and comparable to what we observed in cdhr1a^-/- mutants by 30+ dpf (Figure 9). The exacerbation of phenotypes in the double mutant further supports our model where cdhr1a and pcdh15b function to anchor cone OSs with CPs. Interestingly, these results also suggest that in the absence of either cdhr1a or pcdh15b, there may be redundant mechanisms that aid in OS-CP anchoring. Perhaps other retinal cadherins can interact with cdhr1a or pcdh15b, albeit not as strongly or efficiently, and delay the early phenotypes until the OSs are fully mature. Taken together, our data along with previous studies strongly supports the hypothesis that in the absence of cdhr1a function, the CP-OS interaction is compromised and thus hampers cone OS integrity.

While the focus of our study was on cone cells, we also characterized effects of cdhr1a loss on rods. Rod OSs, nor their CPs appear to be significantly affected by the loss of cdhr1a function until later stages, 3 months or longer (Figures 6 and 7). Albeit significant, these effects were much less obvious compared to the effects on cones, as one might expect for a CRD model. Furthermore, while cone CPs displayed gross morphological defects, rod CPs were only slightly affected even at later timepoints (Figures 6 and 7). This likely stems from the fact that rod CPs are inherently much smaller than cone CPs and may not serve as critical a role in rods as we predict they do in cones (Sahly et al., 2012; Sharkova et al., 2024; Miles et al., 2021; Schietroma et al., 2017). Comparing rod CP length over the course of development and adulthood in our study, we note that rod CPs are on average approximately one third the size of cone CPs (Figure 7). Furthermore, compared to the length of rod OS, rod CPs encompass a very small portion of the OS, while cone CPs extend up to three quarters of the cone OS length. Based on these observations of rod CPs, we hypothesize that zebrafish rod CPs only extend along the newly forming OS discs and do not provide structural support to the ROS. As such, we support the hypothesis postulated by Burgoyne et al., 2015 that in rods, cdhr1a functions to anchor newly formed OS discs to facilitate proper maturation of the discs prior to release into the OS. While this differs from its function in cones, cdhr1a still likely relies on its interaction with pcdh15b to serve this function as the two proteins clearly juxtapose in rod cells across all the species we examined, including rodents which have been hypothesized to lack CPs or have very simplified versions of CPs compared to other species (Sahly et al., 2012).

The discovery of the interaction between cdhr1a and pcdh15b is novel. Previous studies have suggested that PCDH15 and CDH23 are binding partners in the retina as they are well known to interact in the inner ear stereocilia (Schietroma et al., 2017). However, our work, and others, have shown that cdh23 is not expressed in zebrafish retina, nor does loss of cdh23 result in ocular phenotypes (Figure 1—figure supplement 1). Work from macaque retina shows cdh23 expression in the OS/IS region but does not display the prototypical CP staining as observed with pcdh15 or actin (Sahly et al., 2012). While several Usher 1 proteins other than pcdh15 have been found to localize to the CP, including harmonin, myosin, and sans, there has been a missing link between pcdh15 in CP and its potential partner the OS, which we now propose to be Cdhr1. In our study, cdhr1a-pcdh15b interactions are supported by immunoprecipitation and cell aggregation assays and by the fact both are cadherin proteins that can facilitate heterophilic interactions (Figure 3). PCDH15 is known to generate cis dimers like cdh23, and as such the cdhr1a-pcdh15b interaction may in fact involve hetero-tetrameric complexes (Elferich et al., 2021). Additional evidence for the cdhr1a-pcdh15b interaction was the observation that cdhr1a localization along the cone OS was significantly impaired in the absence of pcdh15b function. At 5 dpf and even more so at 10 dpf, the length of cdhr1a signal along the cone OS was severely reduced, while cone OS length was only slightly affected (Figure 9). Thus, we conclude that while pcdh15b is not necessary for cdhr1a to localize to the base of cone OSs, its absence prevents cdhr1a from forming connections to the CP and subsequently extending along the length of the OS. Other proteins may further regulate cdhr1a-pcdh15b complexes such as prom1b, which is known to interact with cdhr1, as well as other Usher 1 proteins found in the CP. CDHR1 is also known to undergo proteolytic cleavage to remove its extracellular cadherin domains, which could further regulate the interaction and stability of the CP-OS attachments (Rattner et al., 2004). It remains unclear if the cleavage occurs in both rod and cone cells. We hypothesize that proteolytic cleavage is specific to rods, where this would aid in regulating the release of the newly matured OS discs, while cleavage would be absent in cone cells to ensure CP-mediated OS structure and integrity. Interestingly, we have also previously reported that cdhr1a can be targeted by the Siah1 ubiquitin ligase for proteasomal degradation, adding yet another layer to the potential complexity of regulating cdhr1a (Piedade and Famulski, 2021). Imaging of siah1 indicates that it also localizes to the OS in a pattern similar to that of cdhr1a (data not shown). Future studies will be required to elucidate the entire complex responsible for the anchoring and maintaining of CPs and OSs in rods versus cones.

Overall, our cdhr1a^-/- model corroborates findings from the mouse CDHR1 KO model with early phenotypes found exclusively in cone cells, and only at later stages, 6+months, displaying rod cell OS disorganization and degeneration. In conclusion, we propose that cdhr1a and pcdh15b function to link the cone OS and the CP to maintain cone homeostasis in an evolutionarily conserved manner. Disruption of this interaction may therefore be a potential driving factor in the progression of CRD observed in CDHR1 patients. Future studies will need to focus on the molecular consequences of OS-CP interaction and the identity of the entire repertoire of proteins involved as well as any potential signaling pathways that activate in response to sensing or monitoring OS-CP interactions.

All data generated or analyzed during this study are included in this published article, source data files have been provided.

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Author details

1. Meet K Patel

   Department of Biology, University of Kentucky, Lexington, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

2. Warlen Pereira Piedade

   Department of Biology, University of Kentucky, Lexington, United States

   Contribution

   Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

3. Jakub K Famulski

   Department of Biology, University of Kentucky, Lexington, United States

   Contribution

   Conceptualization, Supervision, Funding acquisition, Methodology, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   jakub.famulski@uky.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-3619-4113

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