Rescuing Z
            <sup>+</sup>
            agrin splicing in
            <i>Nova</i>
            null mice restores synapse formation and unmasks a physiologic defect in motor neuron firing

Ruggiu, Matteo; Herbst, Ruth; Kim, Natalie; Jevsek, Marko; Fak, John; Mann, Mary Anne; Fischbach, Gerald D.; Burden, Steven J.; Darnell, Robert B.

doi:10.1073/pnas.0813112106

Cited by 110 publications

(117 citation statements)

References 48 publications

Supporting

Mentioning

113

Contrasting

Order By: Relevance

“…SMN functions in snRNP biogenesis as part of the SMN-Gemins complex (16,20) and SMN deficiency causes tissue-specific snRNA repertoire perturbations (15,26), which likely elicit the mRNA expression and splicing abnormalities found in MNs and WM at this early presymptomatic stage. We have not detected changes in mRNAs encoding neuronspecific splicing factors, such as Nova1/2, which can regulate agrin's Z exon splicing (56), or neural polypyrimidine tract-binding proteins (57) at P1. However, abnormalities detected in several other transcription and splicing factors (e.g., Etv1, Fos, Trp53, Tra2b and Celf3) (Datasets S2-S4) could potentially explain why the transcriptome defects in SMA exacerbate over time (15,28).…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy

Zhang

Pinto

Wan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

161

140

View full text Add to dashboard Cite

The motor neuron (MN) degenerative disease, spinal muscular atrophy (SMA) is caused by deficiency of SMN (survival motor neuron), a ubiquitous and indispensable protein essential for biogenesis of snRNPs, key components of pre-mRNA processing. However, SMA's hallmark MN pathology, including neuromuscular junction (NMJ) disruption and sensory-motor circuitry impairment, remains unexplained. Toward this end, we used deep RNA sequencing (RNA-seq) to determine if there are any transcriptome changes in MNs and surrounding spinal cord glial cells (white matter, WM) microdissected from SMN-deficient SMA mouse model at presymptomatic postnatal day 1 (P1), before detectable MN pathology (P4-P5). The RNA-seq results, previously unavailable for SMA at any stage, revealed cell-specific selective mRNA dysregulations (∼300 of 11,000 expressed genes in each, MN and WM), many of which are known to impair neurons. Remarkably, these dysregulations include complete skipping of agrin's Z exons, critical for NMJ maintenance, strong upregulation of synapse pruning-promoting complement factor C1q, and down-regulation of Etv1/ER81, a transcription factor required for establishing sensory-motor circuitry. We propose that dysregulation of such specific MN synaptogenesis genes, compounded by many additional transcriptome abnormalities in MNs and WM, link SMN deficiency to SMA's signature pathology.transcriptome perturbations | Z+ (neuronal) agrin | C1q complex S pinal muscular atrophy (SMA) is an autosomal recessive motor neuron (MN) degenerative disease and a leading genetic cause of infant mortality (1, 2). SMA is caused by deletions or point mutations in the survival of motor neurons 1 gene (SMN1) (3), exposing a splicing defect in a duplicated gene (SMN2), which produces predominantly exon 7-skipped mRNA (SMNΔ7) (4). This in turn creates a degron that destabilizes the SMNΔ7 protein, resulting in reduced SMN levels (SMN deficiency) (5). SMA pathology has been extensively characterized in patients as well as a widely used SMA mouse model (6). Major morphological and biochemical deficits have been found at neuromuscular junctions (NMJs) and sensory-motor synapses. NMJ defects are first detectable at postnatal day 5 (P5), including presynaptic defects of terminal arborization and intermediate neurofilament aggregation in MNs, poor postsynaptic organization of AChRs in muscle, as well as reduced synaptic vesicle density and release at the NMJ (7-9). Importantly, similar NMJ defects have been reported in type I (the most severe type) SMA human fetuses (10). SMA MNs have also been shown to be hyperexcitable and loss of proprioceptive synapses on the somata, and proximal dendrites of SMA MNs (MN deafferentation) occurs no later than P4 (11-13). These findings indicate that both peripheral (NMJs) and central (sensory-motor) synapses are affected in SMA mice at early stage of disease. Although SMA is clinically manifested primarily in MNs, recent studies have shown that other cell types and nonneuronal tissues are also involved (13,14,15). SMN,...

show abstract

Section: Discussionmentioning

confidence: 99%

Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy

Zhang

Pinto

Wan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

161

140

View full text Add to dashboard Cite

show abstract

“…Similar approaches can be used to interrogate isoforms in AS regulatory networks, and recent examples emerging from genetic analysis of Nova-regulated AS events illustrate their power. For example, phenotypic analyses of Nova knockout mice have revealed defects in neuromuscular junction (NMJ) morphology and impaired neuronal migration during development (Ruggiu et al 2009;Yano et al 2010). The aforementioned approaches used to identify Nova-regulated isoforms identified target exons in agrin and disabled-1 transcripts, which are genes with known roles in NMJ formation and neuronal migration, respectively.…”

Section: Determining the Role Of Tissue-specific Isoformsmentioning

confidence: 99%

Networking in a global world: Establishing functional connections between neural splicing regulators and their target transcripts

Calarco¹,

Zhen²,

Blencowe³

2011

RNA

View full text Add to dashboard Cite

Recent genome-wide analyses have indicated that almost all primary transcripts from multi-exon human genes undergo alternative pre-mRNA splicing (AS). Given the prevalence of AS and its importance in expanding proteomic complexity, a major challenge that lies ahead is to determine the functional specificity of isoforms in a cellular context. A significant fraction of alternatively spliced transcripts are regulated in a tissue-or cell-type-specific manner, suggesting that these mRNA variants likely function in the generation of cellular diversity. Complementary to these observations, several tissue-specific splicing factors have been identified, and a number of methodological advances have enabled the identification of large repertoires of target transcripts regulated by these proteins. An emerging theme is that tissue-specific splicing factors regulate coherent sets of splice variants in genes known to function in related biological pathways. This review focuses on the recent progress in our understanding of neural-specific splicing factors and their regulatory networks and outlines existing and emerging strategies for uncovering important biological roles for the isoforms that comprise these networks.

show abstract

“…These studies demonstrate that the complexity involved in the formation of this simple, large peripheral synapse is only beginning to be unravelled. For example, the NMJ defects in Nova1 and Nova2 mutant mice cannot be rescued by overexpressing neuronal agrin in motoneurons (Ruggiu et al, 2009), suggesting the existence of additional neuronal factors.Mutations in and/or autoimmune reactions to some proteins essential for NMJ development cause muscular dystrophies, including myasthenia gravis and congenital myasthenic syndrome (reviewed by Engel et al, 2008). Studies of NMJ formation could identify potential culprits and therapeutic targets for these disorders.…”

mentioning

confidence: 99%

“…Direct interactions between nerve terminals and muscle fibers might be mediated by adhesion molecules, including neural cell adhesion molecule [NCAM (Polo-Parada et al, 2004)], CD24 [a glycosylphosphatidylinositol (GPI)-linked protein (Jevsek et al, 2006)], the immunoglobin proteins Syg1 and Syg2 (Shen and Bargmann, 2003;Shen et al, 2004), and embigin (Lain et al, 2009). However, the mechanisms by which NMJ development is regulated by cell adhesion remain to be elucidated.Finally, recent studies have identified several genes the mutation of which leads to NMJ development defects, including the neuronspecific splicing factors Nova1 and Nova2 (Ruggiu et al, 2009), amyloid precursor protein (APP) , dystrophinassociated proteins (Adams et al, 2004; Banks et al, 2009;Grady et al, 2000;Grady et al, 2003), the glycosyltransferase Large , the protein degradation components Fbxo45, Nedd4, Usp14 and Uchl1 (Chen et al, 2009;Chen et al, 2010;Liu et al, 2009;Saiga et al, 2009), the chromatin organization protein HP1 (Aucott et al, 2008) and meltrin b, a metalloprotease (Yumoto et al, 2008). These studies demonstrate that the complexity involved in the formation of this simple, large peripheral synapse is only beginning to be unravelled.…”

mentioning

confidence: 99%

To build a synapse: signaling pathways in neuromuscular junction assembly

2010

View full text Add to dashboard Cite

SummarySynapses, as fundamental units of the neural circuitry, enable complex behaviors. The neuromuscular junction (NMJ) is a synapse type that forms between motoneurons and skeletal muscle fibers and that exhibits a high degree of subcellular specialization. Aided by genetic techniques and suitable animal models, studies in the past decade have brought significant progress in identifying NMJ components and assembly mechanisms. This review highlights recent advances in the study of NMJ development, focusing on signaling pathways that are activated by diffusible cues, which shed light on synaptogenesis in the brain and contribute to a better understanding of muscular dystrophy. Key words: Neural development, Neuromuscular junction, Retrograde signaling, Synapse formation IntroductionThe brain contains billions of nerve cells, or neurons, which receive and integrate signals from the environment, and which govern the body's responses. Nervous system activity is made possible by synapses, contacts formed either between neurons or between a neuron and a target cell. Synapses are asymmetric structures in which neurotransmitter molecules are released from the presynaptic membrane and activate receptors on the postsynaptic membrane, thus establishing neuronal communication. As such, synapses are fundamental units of neural circuitry and enable complex behaviors. The neuromuscular junction (NMJ) is a type of synapse formed between motoneurons and skeletal muscle fibers. Large and easily accessed experimentally, this peripheral synapse has contributed greatly to the understanding of the general principles of synaptogenesis and to the development of potential therapeutic strategies for muscular disorders. The NMJ uses different neurotransmitters in different species; for example, acetylcholine (ACh) in vertebrates and glutamate in Drosophila, both of which are excitatory and cause muscle contraction. In Caenorhabditis elegans, there are two types of NMJs: at excitatory NMJs, ACh causes muscle contraction, whereas inhibitory NMJs release g-aminobutyric acid (GABA) to cause muscle relaxation. Motor nerve terminals differentiate to form presynaptic active zones, where synaptic vesicles dock and release neurotransmitters. On the apposed postsynaptic membranes, neurotransmitter receptors are packed at high densities. Aided by genetic techniques and by the use of suitable animal models, including rodents, zebrafish, Drosophila and C. elegans, studies in the past decade have brought significant progress, not only in identifying components present in pre-and postsynaptic membranes, but also in understanding the mechanisms that underpin NMJ assembly. This review highlights recent advances in the study of NMJ development, focusing on signaling pathways that are activated by diffusible cues from motor nerves and muscle fibers. Readers are referred to other outstanding reviews for a broad view of NMJ development (see Froehner, 1993;Hall and Sanes, 1993;Kummer et al., 2006;Salpeter and Loring, 1985;Schaeffer et al., 2001). NMJ formati...

show abstract

Rescuing Z ⁺ agrin splicing in Nova null mice restores synapse formation and unmasks a physiologic defect in motor neuron firing

Cited by 110 publications

References 48 publications

Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy

Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy

Networking in a global world: Establishing functional connections between neural splicing regulators and their target transcripts

To build a synapse: signaling pathways in neuromuscular junction assembly

Contact Info

Product

Resources

About

Rescuing Z + agrin splicing in Nova null mice restores synapse formation and unmasks a physiologic defect in motor neuron firing

Cited by 110 publications

References 48 publications

Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy

Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy

Networking in a global world: Establishing functional connections between neural splicing regulators and their target transcripts

To build a synapse: signaling pathways in neuromuscular junction assembly

Contact Info

Product

Resources

About

Rescuing Z ⁺ agrin splicing in Nova null mice restores synapse formation and unmasks a physiologic defect in motor neuron firing