Department of Biology

University of Kentucky

Lexington, KY

BASIC RESEARCH PROJECT

Analyzing the functional role of calycleal processes in DCHR1-dependent cone rod dystrophy

Research Interests

This project seeks to enhance our understanding of the molecular mechanisms underlying cone-rod dystrophy (CRD), particularly in relation to the loss of CDHR1 function. CDHR1 is a specialized protein found in the retina and has been linked to CRD in many human patients. It is believed that CDHR1 plays a role in connecting newly forming rod outer segment discs to the inner segment, influencing their maturation and release. However, how the loss of CDHR1 leads to CRD, especially in relation to cone photoreceptors and how they are affected is still not fully understood.

Plans for 2026

In his efforts to decipher CDHR1’s role in zebrafish cones, Dr. Famulski made a novel discovery. His lab found that CDHR1 may form connections between photoreceptor outer segments and inner membrane extensions called calyceal processes by physically interacting with a specific cadherin called Pcdh15b. Based on this finding, the Famulski lab aims to test the hypothesis that these connections are essential for maintaining and assembling rod and cone outer segments, and that their disruption leads to CRD.

Specific Aims: To complete and expand aim 1 from the 2024 application and based on our progress

1. Comprehensively analyze functionality of CRD patient CDHR1 mutations.
2. Characterize novel CDHR1 interaction partners
3. Identify the PCDH15 calyceal process interactome.

Progress in 2025

Thoughout 2025, Dr. Famulski’s lab successfully completed his project’s Aims 2-4, while  continuing to work on Aim 1. Based on recent findings, this aim has been expanded with additional approaches. In short, the lab has a) characterized gene expression changes in cone cells lacking cdhr1a, b) visualized cdhr1a localizing at sites of outer segment and calyceal process connections using Transmission Electron Microscopy and c) identified novel interacting partners with CDHR1’s cytoplasmic domain.

Progress in 2024

Dr. Famulski successfully completed aims 1 and 2, which became the basis of his recent publication in eLife. In short, the Famulski laboratory has shown that cdhr1a and pcdh15b form functional connections between outer segments and calyceal processes and that their absence leads to cone OS degeneration. They made progress on aims 3 and 4 by establishing a robust immune-gold TEM protocol and generating a transgenic bioID construct for identifying cdhr1a partners.

To test their hypothesis, they created a zebrafish mutant with a non-functional cdhr1a gene, which exhibits key features of CRD, including early and severe degeneration of cone photoreceptors and delayed degeneration of rods. They proposed the following aims:

1. Characterize the integrity of calyceal processes in the absence of Cdhr1a function.
2. Examine the functionality of Cdhr1a-Pcdh15b interactions.
3. Visualize interactions between Cdhr1a and Pchd15b in photoreceptors in vivo.
4. Identify the cdhr1a outer segment interactome.

Overall, Dr. Famulski’s project aims to comprehensively study the interaction between outer segments (via cdhr1a) and calyceal processes (via pchd15b) to establish a novel mechanism critical for maintaining outer segment health and preventing CRD. His team’s research may also uncover additional genes involved in this mechanism, potentially identifying new target genes associated with CRD.