Biology subjects

Hussey, K.

Publications and source records attributed to Hussey, K..

3 recordsLinked to original sources

bioRxiv2025

Complement Factor H and its C. elegans homolog regulate IFT52/OSM-6 and CNG channel localization in sensory neurons

Age-related macular degeneration (AMD), the leading cause of blindness in the elderly, is characterized by progressive degeneration of retinal photoreceptors. Current disease models propose AMD pathogenesis is a consequence of cytolytic damage and tissue inflammation that result from defective repression of alternative complement pathway activity by complement factor H (CFH). However, recent studies demonstrate functions for CFH that are outside of its established role in the alternative complement pathway, suggesting that novel CFH-mediated mechanisms may influence AMD initiation and progression. Our previous demonstration that CFH and its nematode homolog, CFH-1, modulate inversin/NPHP-2 accumulation in vertebrate photoreceptor and C. elegans sensory neuron cilia during aging suggests that AMD patients with CFH loss-of-function mutations have cilia defects that may contribute to photoreceptor dysfunction. Here, we investigate the consequences of CFH and CFH-1 loss-of-function mutations on the dynamics and localization of intraflagellar transport (IFT) train and visual cycle components in these cells. In C. elegans sensory neurons, IFTB1 components IFT52/OSM-6 and IFT88/OSM-5 are transported at similar rates in WT animals but IFT52/OSM-6 transport slows significantly in cfh-1 mutant animals while IFT88/OSM-5 is unaffected. Defective localization of IFT52/OSM-6 in photoreceptors of CFH knockout mice and in human photoreceptors from AMD high-risk CFH Y402H homozygotes, suggest an evolutionarily conserved role for CFH in promoting IFT52/OSM-6 transport and localization in sensory neuron cilia. In addition, distribution of CNG channel subunits in C. elegans cfh-1 mutant sensory neurons and CFH Y402H high-risk human photoreceptors are distinct from their WT and Y402 low-risk counterparts. Together, the data indicate previously unappreciated functions for CFH in IFT train organization and cilia protein localization and suggest a novel mechanism for photoreceptor segment thinning, an early AMD biomarker that has been linked to CFH high-risk variants.

cell biology↗

bioRxiv2023

Foveolar cone subtype patterning in human retinal organoids

The mechanisms that generate patterns of cell types unique to humans are poorly understood. In the central region of the human retina, the high-acuity foveola is notable, in part, for its dense packing of green (M) and red (L) cones and absence of blue (S) cones. To identify mechanisms that promote M/L and suppress S cone patterning in the foveola, we examined human fetal retinas and differentiated human retinal organoids. During development, sparse S-opsin-expressing cones are initially observed in the foveola. Later in fetal development, the foveola contains a mix of cones that either co-express S- and M/L-opsins or exclusively express M/L-opsin. In adults, only M/L cones are present. Two signaling pathway regulators are highly and continuously expressed in the central retina: Cytochrome P450 26 subfamily A member 1 (CYP26A1), which degrades retinoic acid (RA) and Deiodinase 2 (DIO2), which promotes thyroid hormone (TH) signaling. Both CYP26A1 null mutant organoids and high RA conditions increased the number of S cones and reduced the number of M/L cones in human retinal organoids. In contrast, sustained TH signaling promoted the generation of M/L-opsin-expressing cones and induced M/L-opsin expression in S-opsin-expressing cones, showing that cone fate is plastic. Our data suggest that CYP26A1 degrades RA to specify M/L cones and limit S cones and that continuous DIO2 expression sustains high levels of TH to convert S cones into M/L cones, resulting in the foveola containing only M/L cones. Since the foveola is highly susceptible to impairment in diseases such as macular degeneration, a leading cause of vision loss, our findings inform organoid design for potential therapeutic applications.

developmental biology↗

bioRxiv2022

Transretinal migration of astrocytes and brain/spinal cord-like cells arising from transplanted human retinal organoids.

Human retinal organoid transplantation can potentially restore vision in patients with degenerative retinal diseases. How the recipient retina regulates the maturation, fate specification, and migration of transplanted organoid cells is unknown. We transplanted human retinal organoid-derived cells into photoreceptor-deficient mice, conducted histology and single-cell RNA sequencing analyses, and observed two main classes of graft-derived cells. The first class consisted of retinal astrocytes and brain/spinal cord-like neural precursors, absent or rare in cultured organoids, that migrated into all recipient retinal layers and traveled long distances. The second class consisted of retinal progenitor-derived cells, including rods and cones, that remained in the subretinal space and matured more rapidly than photoreceptors in culture. These data suggest that the recipient subretinal space promotes the maturation of transplanted photoreceptors while inducing or expanding migratory cell populations that are not normally derived from retinal progenitors. These findings have important implications for cell-based treatment of retinal diseases.

neuroscience↗