Conserved and divergent processing of neuroligin and neurexin genes: from the nematode C. elegans to human

Abstract

Neuroligins are cell-adhesion proteins that interact with neurexins at the synapse. This interaction may contribute to differentiation, plasticity and specificity of synapses. In humans, single mutations in neuroligin-encoding genes are implicated in autism spectrum disorder and/or mental retardation. Moreover, some copy number variations and point mutations in neurexin-encoding genes have been linked to neurodevelopmental disorders including autism. Neurexins are subject to extensive alternative splicing, highly regulated in mammals, with a great physiological importance. In addition, neuroligins and neurexins are subjected to proteolytic processes that regulate synaptic transmission modifying pre- and postsynaptic activities and may also regulate the remodelling of spines at specific synapses. Four neuroligin genes exist in mice and five in human, whilst in the nematode Caenorhabditis elegans, there is only one orthologous gene. In a similar manner, in mammals, there are three neurexin genes, each of them encoding two major isoforms named α and β, respectively. In contrast, there is one neurexin gene in C. elegans that also generates two isoforms like mammals. The complexity of the genetic organization of neurexins is due to extensive processing resulting in hundreds of isoforms. In this review, a wide comparison is made between the genes in the nematode and human with a view to better understanding the conservation of processing in these synaptic proteins in C. elegans, which may serve as a genetic model to decipher the synaptopathies underpinning neurodevelopmental disorders such as autism.

Analysis of splice variants for the C. elegans orthologue of human neuroligin reveals a developmentally regulated transcript

“…Although the gene organization of neuroligins is not conserved between C. elegans and mammals the overall domain architecture is well conserved (Fig. 1A) (Calahorro, 2014;Calahorro and Ruiz-Rubio, 2012). There is only one C. elegans neuroligin while there are 4 or 5 separate genes in mammals and human respectively (Fig.…”

“…The vertebrate and mammalian neuroligins are evolutionarily more distant from the C. elegans neuroligin. However, the core protein including the cholinesteraselike domain and O-linked and N-linked glycosylation sites are conserved between mammals and the nematode (Calahorro, 2014 (Fig. 1B).…”

“…Rare variants in the human genes encoding postsynaptic neuroligin-3 and 4 (NLGN-3 and -4), and their presynaptic binding partner neurexin-1 (NRXN-1) have been linked with autism spectrum disorders (ASD) (Sudhof, 2008). The human neurexin and neuroligin genes are orthologous to the Caenorhabditis elegans genes nrx-1 and nlg-1, respectively (Calahorro, 2014).…”

“…Additionally, NLGN-1 presents another splice position (splice site B, SSB) in exon 5 that encodes the central region of the acetylcholinesterase domain (Calahorro, 2014;Ichtchenko et al, 1995Ichtchenko et al, , 1996. Functional impact of these differences is indicated by in vitro observations that NLGN-1 lacking SSB induce a rapid presynaptic differentiation of approaching neurons relative to the full length NLGN-1.…”

Molecular Architecture of Genetically-Tractable GABA Synapses in C. elegans

“…NLG-1 shares about 25% identity with human NLs and cannot be related to one specific paralog. However, the core protein organization is conserved between mammals and the nematode (Calahorro, 2014). Three main NLG-1 isoforms are generated by alternative splicing of exons encoding cytoplasmic domains of the protein (Calahorro et al, 2015).…”