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Abstract
Neuronal communication is typically mediated via synapses and gap junctions. New forms of intercellular communication, including nanotubes (NTs) and extracellular vesicles (EVs), have been described for non‐neuronal cells, but their role in neuronal communication is not known. Recently, transfer of cytoplasmic material between donor and host neurons (“material transfer”) was shown to occur after photoreceptor transplantation. The cellular mechanism(s) underlying this surprising finding are unknown. Here, using transplantation, primary neuronal cultures and the generation of chimeric retinae, we show for the first time that mammalian photoreceptor neurons can form open‐end NT‐like processes. These processes permit the transfer of cytoplasmic and membrane‐bound molecules in culture and after transplantation and can mediate gain‐of‐function in the acceptor cells. Rarely, organelles were also observed to transfer. Strikingly, use of chimeric retinae revealed that material transfer can occur between photoreceptors in the intact adult retina. Conversely, while photoreceptors are capable of releasing EVs, at least in culture, these are taken up by glia and not by retinal neurons. Our findings provide the first evidence of functional NT‐like processes forming between sensory neurons in culture and in vivo.
Highlights
Intercellular communication is an essential process for the development and maintenance of all tissues, including the nervous system
We examined the ultrastructure of early postnatal wildtype retinae and found that the photoreceptors often presented with multivesicular bodies (MVBs; ~ 500 nm diameter; 1–2 MVBs/photoreceptor at postnatal day 7) containing intraluminal vesicles (ILVs) (Fig 1A), which can be released as extracellular vesicles (EVs)
As assessed by flow cytometry (Figs 5A and EV3A), a proportion of cells exhibited detectable levels of both labels (~ 4% at 21DIV, increasing over time; Fig 5A), consistent with previous observations regarding NT-like protrusions in other cell types (Rustom et al, 2004). These results indicate that fluorescent cytoplasmic molecules can be exchanged between photoreceptor nanotubes (PhNTs)-connected photoreceptor cells in vitro, but that this is likely to be a transient process occurring in a relative minority of cells at any given point in time, consistent with material transfer events occurring after photoreceptor transplantation (Pearson et al, 2016)
Summary
Intercellular communication is an essential process for the development and maintenance of all tissues, including the nervous system. A variety of membranous processes have been described in diverse organisms, including echinoids (where they have been termed as specialized filopodia) (Gustafson & Wolpert, 1967), flies (cytonemes) (Ramirez-Weber & Kornberg, 1999), birds (cytoplasmic bridges) (Teddy & Kulesa, 2004; George et al, 2016) and mammals (nanotubes) (Rustom et al, 2004; Chinnery et al, 2008) These processes can facilitate the exchange of molecules in culture and in vivo during early embryo development (for reviews, see (Korenkova et al, 2020; Ljubojevic et al, 2021)). Existing either as actin-enriched open-end tubes or closed-tip filopodia-like protrusions, these processes have been reported to transfer Ca2+ (Alarcon-Martinez et al, 2020), morphogens (Chen et al, 2017), fluorescent reporters (Kulesa et al, 2010; McKinney & Kulesa, 2011), vesicles (Gradilla et al, 2014), mRNA (Haimovich et al, 2017) and even organelles (Rustom et al, 2004; Alarcon-Martinez et al, 2020) between cells
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