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Fernando Calahorro 《Invertebrate neuroscience : IN》2014,14(2):79-90
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. 相似文献
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The Making of Neurexins 总被引:14,自引:2,他引:12
Markus Missler Rafael Fernandez-Chacon Thomas C. Südhof 《Journal of neurochemistry》1998,71(4):1339-1347
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RIMs are synaptic proteins that are essential for normal neurotransmitter release. We now show that while invertebrates contain only a single RIM gene, vertebrates contain four: two large genes encoding RIM1alpha (0.50 Mb) or RIM2alpha, 2beta, and 2gamma (0.50-0.75 Mb) and two smaller genes encoding RIM3gamma (14 kb) or RIM4gamma (55 kb). RIM1alpha and RIM2alpha consist of an N-terminal Zn(2+)-finger domain, central PDZ and C(2)A domains, and a C-terminal C(2)B domain; RIM2beta consists of a short beta-specific sequence followed by central PDZ and C(2)A domains and a C-terminal C(2)B domain; and RIM2gamma, 3gamma, and 4gamma consist of only a C(2)B domain. In the RIM2 gene, RIM2beta and 2gamma are transcribed from internal promoters. alpha- and beta-RIMs are extensively alternatively spliced at three canonical positions, resulting in >200 variants that differ by up to 400 residues. Thus gene duplication, alternative splicing, and multiple promoters diversify a single invertebrate RIM into a large vertebrate protein family. The multiplicity of vertebrate RIMs may serve to fine-tune neurotransmitter release beyond a fundamental, evolutionarily conserved, and common function for RIMs. 相似文献
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A splice code for trans-synaptic cell adhesion mediated by binding of neuroligin 1 to alpha- and beta-neurexins 总被引:11,自引:0,他引:11
Previous studies suggested that postsynaptic neuroligins form a trans-synaptic complex with presynaptic beta-neurexins, but not with presynaptic alpha-neurexins. Unexpectedly, we now find that neuroligins also bind alpha-neurexins and that alpha- and beta-neurexin binding by neuroligin 1 is regulated by alternative splicing of neuroligin 1 (at splice site B) and of neurexins (at splice site 4). In neuroligin 1, splice site B is a master switch that determines alpha-neurexin binding but leaves beta-neurexin binding largely unaffected, whereas alternative splicing of neurexins modulates neuroligin binding. Moreover, neuroligin 1 splice variants with distinct neurexin binding properties differentially regulate synaptogenesis: neuroligin 1 that binds only beta-neurexins potently stimulates synapse formation, whereas neuroligin 1 that binds to both alpha- and beta-neurexins more effectively promotes synapse expansion. These findings suggest that neuroligin binding to alpha- and beta-neurexins mediates trans-synaptic cell adhesion but has distinct effects on synapse formation, indicating that expression of different neuroligin and neurexin isoforms specifies a trans-synaptic signaling code. 相似文献
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Analysis of the human neurexin genes: alternative splicing and the generation of protein diversity 总被引:10,自引:0,他引:10
Rowen L Young J Birditt B Kaur A Madan A Philipps DL Qin S Minx P Wilson RK Hood L Graveley BR 《Genomics》2002,79(4):587-597
The neurexins are neuronal proteins that function as cell adhesion molecules during synaptogenesis and in intercellular signaling. Although mammalian genomes contain only three neurexin genes, thousands of neurexin isoforms may be expressed through the use of two alternative promoters and alternative splicing at up to five different positions in the pre-mRNA. To begin understanding how the expression of the neurexin genes is regulated, we have determined the complete nucleotide sequence of all three human neurexin genes: NRXN1, NRXN2, and NRXN3. Unexpectedly, two of these, NRXN1 ( approximately 1.1 Mb) and NRXN3 ( approximately 1.7 Mb), are among the largest known human genes. In addition, we have identified several conserved intronic sequence elements that may participate in the regulation of alternative splicing. The sequences of these genes provide insight into the mechanisms used to generate the diversity of neurexin protein isoforms and raise several interesting questions regarding the expression mechanism of large genes. 相似文献
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The incomplete correlation between the organismal complexities and the number of genes among eukaryotic organisms can be partially
explained by multiple protein products of a gene created by alternative splicing. One type of alternative splicing involves
alternative selection of mutually exclusive exons and creates protein products with substitution of one segment of the amino
acid sequence for another. To elucidate the evolution of the mutually exclusive 115-bp exons, designated flip and flop, of
vertebrate AMPA receptor genes, the gene structures of chordate (tunicate, cephalochordate, and vertebrate) and protostome
(Drosophila and Caenorhabditis elegans) AMPA receptor subunits were compared. Phylogenetic analysis supports that the vertebrate flip and flop exons evolved from
a common sequence. Flip and flop exons exist in all vertebrate AMPA receptor genes but only one 115-bp exon is present in
the genes of tunicates and cephalochordates, suggesting that the exon duplication event occurred at the ancestral vertebrate
AMPA receptor gene after the separation of vertebrates from primitive chordates. The structures of animal AMPA receptor genes
also suggest that an intron insertion to separate the primordial flip/flop exon from the M4-coding exon occurred before the
exon duplication event and probably at the chordate lineage.
[Reviewing Editor: Dr. Manyuan Long] 相似文献
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RNA interference (RNAi) is the process of sequence-specific gene silencing. However, RNAi efficiency still needs to be improved for effective inhibition of target genes. We have developed an effective strategy to express multiple shRNAs (small hairpin RNA) simultaneously using multiple RNA Polymerase III (Pol III) promoters in a single vector. Our data demonstrate that multiple shRNAs expressed from Pol III promoters have a synergistic effect in repressing the target gene. Silencing of endogenous cyclophilin A (CypA) or key HIV viral genes by multiple shRNAs results in significant inhibition of the target gene. 相似文献
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In this issue of Cell, Axel and colleagues (Lomvardas et al., 2006) report that a single enhancer of an odorant receptor (OR) gene cluster interacts with multiple OR gene promoters on different chromosomes. This study suggests a mechanism that allows olfactory sensory neurons to choose randomly and express only one out of more than 1000 OR genes. 相似文献
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Human promoters divide into 2 classes, the low CpG (LCG) and the high CpG (HCG), based on their CpG dinucleotide content. The LCG class of promoters is hypermethylated and is associated with tissue-specific genes, whereas the HCG class is hypomethylated and associated with broadly expressed genes. By analyzing several chordate genomes separated for hundreds of millions of years, here we show that the divide between low CpG and high CpG promoters is conserved in several distantly related vertebrate taxa (including human, chicken, frog, lizard, and fish) but not in close invertebrate outgroups (sea squirts). Furthermore, LCG and HCG promoters are distinctively associated with tissue-specific and broadly expressed genes in these distantly related vertebrate taxa. Our results indicate that the function of DNA methylation on gene expression is conserved across these vertebrate taxa and suggest that the 2 classes of promoters have evolved early in vertebrate evolution, as a consequence of the advent of global DNA methylation. 相似文献
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Structure and expression of the nuclear gene coding for the chloroplast ribosomal protein L21: developmental regulation of a housekeeping gene by alternative promoters. 总被引:8,自引:0,他引:8
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T Lagrange B Franzetti M Axelos R Mache S Lerbs-Mache 《Molecular and cellular biology》1993,13(4):2614-2622
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We have determined the genomic structure of an integrin β-subunit gene from the coral, Acropora millepora. The coding region of the gene contains 26 introns, spaced relatively uniformly, and this is significantly more than have
been found in any integrin β-subunit genes from higher animals. Twenty-five of the 26 coral introns are also found in a β-subunit
gene from at least one other phylum, indicating that the coral introns are ancestral. While there are some suggestions of
intron gain or sliding, the predominant theme seen in the homologues from higher animals is extensive intron loss. The coral
baseline allows one to infer that a number of introns found in only one phylum of higher animals result from frequent intron
loss, as opposed to the seemingly more parsimonious alternative of isolated intron gain. The patterns of intron loss confirm
results from protein sequences that most of the vertebrate genes, with the exception of β4, belong to one of two β subunit
families. The similarity of the patterns within each of the β1,2,7 and β3,5,6,8 groups indicates that these gene structures
have been very stable since early vertebrate evolution. Intron loss has been more extensive in the invertebrate genes, and
obvious patterns have yet to emerge in this more limited data set.
Received: 5 March 2001 / Accepted: 17 May 2001 相似文献
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