Date of Award
Level of Access
Doctor of Philosophy (PhD)
Patsy M. Nishina
Second Committee Member
Gregory A. Cox
Third Committee Member
Additional Committee Members
Stephen H. Tsang
The retina, as a critical component of the sensory system, consists of multiple cell types, of which, photoreceptors play a key role in receiving, integrating and transmitting light signals. The biofunctions of photoreceptors rely on their proper growth and development, which is predominantly governed by a cluster of molecules that comprise the transcriptional regulation for photoreceptor development. Any disruption of these molecules potentially incurs retinal pathologies.
It is known that deficiencies of nuclear receptor subfamily 2 group E member 3 (NR2E3) or neural retina leucine-zipper (NRL), two molecules in regulating photoreceptor cell development, cause photoreceptor dysplasia. In a sensitized chemical mutagenesis study to identify genetic modifiers in retinal degeneration (rd) 7 mice (Nr2e3rd7), Tvrm222, was established, in which photoreceptor dysplasia was significantly rescued compared to that in Nr2e3rd7 mutants. Notably, the Tvrm222 allele also ameliorates photoreceptor dysplasia in Nrl knockout mice. According to whole-genome mapping and exome sequencing, the modifier was localized to Chromosome 6 and was identified as a missense variant in the FERM domain containing 4B (Frmd4b) gene, which is predicted to cause the substitution of serine residue 938 with proline (S938P).
Furthermore, we observed that the Frmd4bTvrm222 allele preserved the integrity of the fragmented external limiting membrane (ELM) present in both rd7 and Nrl–/– mouse retinas. FRMD4B, as a binding partner of cytohesin 3 (CYTH3), has been proposed to participate in cell junction remodeling. However, its function in ELM maintenance and photoreceptor dysplasia has not been previously examined. This study revealed that the S938P variation significantly reduces in vitro membrane recruitment of FRMD4B.
Notably, in an attempt to explore the molecular mechanisms underlying the modifying effect of FRMD4B938P on dysplastic retinas, we observed an increased activation of ADP-ribosylation factor 6, a direct substrate for CYTH3, both in vitro and in vivo, as well as decreased phosphorylation of AKT in Tvrm222 retinas. These changes were accompanied by an elevation in cell membrane-associated zonula adherens and occludens proteins in Tvrm222 retinas. Taken together, this study determines a critical role of FRMD4B in maintaining the integrity of adhesive support (at the ELM) and in rescuing photoreceptor dysplasia in mice.
Kong, Yang, "Genetic Modification of Inherited Retinopathy in Mice" (2018). Electronic Theses and Dissertations. 2901.
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