Abstract
Genome sequence comparisons have highlighted many novel gene families that are conserved across animal phyla but whose biological function is unknown. Here, we functionally characterize a member of one such family, the macoilins. Macoilins are characterized by several highly conserved predicted transmembrane domains towards the N-terminus and by coiled-coil regions C-terminally. They are found throughout Eumetazoa but not in other organisms. Mutants for the single Caenorhabditis elegans macoilin, maco-1, exhibit a constellation of behavioral phenotypes, including defects in aggregation, O2 responses, and swimming. MACO-1 protein is expressed broadly and specifically in the nervous system and localizes to the rough endoplasmic reticulum; it is excluded from dendrites and axons. Apart from subtle synapse defects, nervous system development appears wild-type in maco-1 mutants. However, maco-1 animals are resistant to the cholinesterase inhibitor aldicarb and sensitive to levamisole, suggesting pre-synaptic defects. Using in vivo imaging, we show that macoilin is required to evoke Ca2+ transients, at least in some neurons: in maco-1 mutants the O2-sensing neuron PQR is unable to generate a Ca2+ response to a rise in O2. By genetically disrupting neurotransmission, we show that pre-synaptic input is not necessary for PQR to respond to O2, indicating that the response is mediated by cell-intrinsic sensory transduction and amplification. Disrupting the sodium leak channels NCA-1/NCA-2, or the N-,P/Q,R-type voltage-gated Ca2+ channels, also fails to disrupt Ca2+ responses in the PQR cell body to O2 stimuli. By contrast, mutations in egl-19, which encodes the only Caenorhabditis elegans L-type voltage-gated Ca2+ channel α1 subunit, recapitulate the Ca2+ response defect we see in maco-1 mutants, although we do not see defects in localization of EGL-19. Together, our data suggest that macoilin acts in the ER to regulate assembly or traffic of ion channels or ion channel regulators.
Highlights
One of the most striking innovations in Metazoa is a nervous system with specialized nerve cells, pre- and post-synaptic structures, and associated signaling molecules
We show that worm macoilin, like mouse macoilin, is expressed widely but in nerve cells
Nerve signalling relies on calcium channels and the defect of macoilin mutants resembles that of animals defective in a particular calcium channel component
Summary
One of the most striking innovations in Metazoa is a nervous system with specialized nerve cells, pre- and post-synaptic structures, and associated signaling molecules. Neuronal signaling depends on complexes of multipass transmembrane proteins such as ion channels and G-protein-coupled receptors. The emerging picture is that neurons have a highly specialized endoplasmic reticulum (ER), allowing channels to undergo quality control prior to export. The extensive intracellular membrane system that makes up the ER varies, depending on cell type, but two domains, the rough and smooth ER (RER and SER), can usually be distinguished. In C. elegans neurons, RER proteins are concentrated in the cell body and excluded from dendrites and axons, whereas general ER proteins are found in both cell body and neurites [4]. Electron microscopy confirms that ribosomes and RER are abundant in the cell body of C. elegans neurons but rare in neurites, whereas smooth ER-like structures can be seen in axons and dendrites as well as the cell body
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
