Biology subjects

Flajnik, M.

Publications and source records attributed to Flajnik, M..

3 recordsLinked to original sources

bioRxiv2026

Cartilaginous fish inform the lineage-specific evolution and MHC association of the TLR family

Chondrichthyans (sharks, rays and chimaeras) diverged from other vertebrate lineages over 400 million years ago and possess fully functional innate and adaptive immune systems. They comprise over 1,200 species occupying diverse aquatic habitats, from fresh to marine waters and from shallow to deep seas. Exposure to diverse pathogens through time, together with contemporary ocean warming and habitat degradation driven by climate change, has likely shaped unique immune mechanisms in these species. Toll-like receptors (TLRs) are central components of innate immunity, recognizing conserved pathogen-associated molecular patterns and initiating immune responses, yet their diversity remains poorly characterized in Chondrichthyans. Here, we characterize the TLR gene repertoire in elasmobranchs (sharks and rays) using genomic and transcriptomic data. We identify orthologs spanning all known vertebrate TLR families, including genes shared with agnathans as well as gnathostome-specific genes, and detect lineage-specific patterns of TLR duplication and loss, particularly in squaliform sharks and rays. Molecular evolution analyses indicate that most elasmobranch TLRs are under strong purifying selection, with positively selected sites in all genes, consistent with ongoing adaptation to pathogen-and environment-driven pressures. Several TLRs co-localize with genomic regions enriched in immune genes, including MHC paralogous regions, suggesting an ancestral genomic hotspot for vertebrate immunity.

evolutionary biology↗

bioRxiv2025

TEP-1, a glial thioester protein is required for cilia organization and intraflagellar transport in ensheathed sensory neurons

Age-related macular degeneration (AMD), the leading cause of blindness in the elderly, is characterized by progressive degeneration of retinal photoreceptors. Traditional disease models suggest that defective repression of thioester protein C3 activity by complement factor H (CFH) is a major contributor to pathogenesis in AMD and a related disease, early-onset drusen maculopathy (EODM). Our previous study identified novel functions for human CFH and C. elegans CFH-1 in the maintenance of inversin compartment integrity in photoreceptors and mechanosensory neurons, indicating that CFH has a novel, evolutionarily conserved role in cilia compartment organization that is distinct from its established function in alternative complement pathway regulation. Here, we investigate the C. elegans thioester protein TEP-1, an ancestral relative of C3 and other members of the AMCOM family (C4, C5, CD109, and alpha-2-macroglobulin). TEP-1 localizes to select glial cell surfaces and regulates inversin compartment organization and intraflagellar transport (IFT) within the cilia of ensheathed sensory neurons. In addition to revealing a novel role for an AMCOM family member in sensory neuron structure and protein transport, the localization of C3 and CFH on human photoreceptors provides support for non-canonical models of AMD and EODM pathogenesis in which defects in cilia structure and protein transport contribute directly to the progressive photoreceptor dysfunction that characterizes these diseases.

cell biology↗

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↗