Compartmentalized Expression of the α- and γ-Subunits of the Acetylcholine Receptor in Recently Fused Myofibers

Piette, Jacques; Huchet, Monique; Houzelstein, Denis; Changeux, Jean‐Pierre

doi:10.1006/dbio.1993.1124

Cited by 23 publications

(18 citation statements)

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“…The first suggestion of such differential transcription came from experiments that showed AChR a-and 6-subunit RNAs to be more abundant in synapse-rich than synapse-free regions of adult muscle (42). Since then, in situ hybridization has confirmed and extended these results, showing a, I, 8, and £ RNAs enriched at the endplate (7,23,24,28,48 Several studies indicate that the unique expression pattern of the £ gene demonstrates stringent nerve-induced, synapsespecific transcription (7,27,38,(67)(68)(69). Unlike the other subunits, E mRNA does not appear in significant amounts until after innervation and is then found only near synaptic nuclei.…”

mentioning

confidence: 82%

“…The first suggestion of such differential transcription came from experiments that showed AChR a-and 6-subunit RNAs to be more abundant in synapse-rich than synapse-free regions of adult muscle (42). Since then, in situ hybridization has confirmed and extended these results, showing a, I, 8, and £ RNAs enriched at the endplate (7,23,24,28,48). Recently, studies of transgenic mice have proven that the concentration of AChR RNA at the synapse is due to enhanced transcription of AChR genes by junctional nuclei.…”

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confidence: 97%

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A novel synapse-associated noncoding RNA.

1994

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We have focused our studies on this third feature of AChR gene regulation, the notion of "privileged" synaptic nuclei that preferentially transcribe AChR genes (see reference 13 for a review). The first suggestion of such differential transcription came from experiments that showed AChR a-and 6-subunit RNAs to be more abundant in synapse-rich than synapse-free regions of adult muscle (42). Since then, in situ hybridization has confirmed and extended these results, showing a, I, 8, and £ RNAs enriched at the endplate (7,23,24,28,48 Several studies indicate that the unique expression pattern of the £ gene demonstrates stringent nerve-induced, synapsespecific transcription (7,27,38,(67)(68)(69). Unlike the other subunits, E mRNA does not appear in significant amounts until after innervation and is then found only near synaptic nuclei. Even after denervation, e RNA remains synaptically localized and its levels do not change significantly, suggesting that endplate nuclei are permanently imprinted. There appears to be a stable signal from the motor nerve, perhaps deposited in the synaptic basal lamina, that induces and maintains preferential transcription of the £ (and a, 3, and 8) genes at synaptic nuclei.The nature of this nerve-derived signal, and the postsynaptic regulatory factors that transduce it, remains largely unknown. Most progress has been made presynaptically with the identification of two putative regulatory factors: calcitonin generelated peptide (44)

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mentioning

confidence: 82%

“…The first suggestion of such differential transcription came from experiments that showed AChR a-and 6-subunit RNAs to be more abundant in synapse-rich than synapse-free regions of adult muscle (42). Since then, in situ hybridization has confirmed and extended these results, showing a, I, 8, and £ RNAs enriched at the endplate (7,23,24,28,48). Recently, studies of transgenic mice have proven that the concentration of AChR RNA at the synapse is due to enhanced transcription of AChR genes by junctional nuclei.…”

mentioning

confidence: 97%

A novel synapse-associated noncoding RNA.

1994

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“…This study suggested that erbB2 and NRG foster development of the heart via a paracrine mechanism. ErbB2 mice die of a trabeculation defect before gliogenesis in the PNS (Lawson and Biscoe, 1979) and before onset of neural muscular junction at E12 (Noakes et al, 1993;Piette et al, 1993). To study the role of erbB2 after E11, we genetically rescued the cardiac defect in erbB2-null mice by creating transgenic mice that expressed rat erbB2 under the control of a cardiac-specific ␣-myosin heavy chain (␣-MHC) promoter (Morris et al, 1999).…”

Section: B Rescue Of the Cardiac Trabeculation In Erbb2-null Micementioning

confidence: 99%

Essential Roles of Her2/erbB2 in Cardiac Development and Function

Negro

Brar²,

Lee³

2004

Recent Progress in Hormone Research

196

123

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The tyrosine kinase receptor erbB2, also known in humans as Her2, is a member of the epidermal growth factor receptor (EGFR or erbB1) family, which also includes erbB3 and erbB4. The erbBs were discovered in an avian erythroblastosis tumor virus and exhibited similarities to human EGFR (Yarden and Sliwkowski, 2001). Her2/erbB2 is highly expressed in many cancer types. Its overexpression is correlated with a poor prognosis for breast and ovarian cancer patients. ErbB receptors bind to a family of growth factors, termed neuregulins/heregulin (NRG/HRG), which comprise NRG-1, -2, -3, and -4 and include multiple isoforms. ErbB2/Her2 is an orphan receptor that does not bind ligand alone but heterodimerizes with the other erbB receptors for NRG signaling. ErbB2 is expressed in multiple neuronal and non-neuronal tissues in embryos and adult animals, including the heart. Genetic data demonstrated that erbB2 is required for normal embryonic development of neural crest-derived cranial sensory neurons. ErbB2/Her2-null mutant embryos of a trabeculation defect die before embryonic day (E) 11. To study its role at later stages of development, we generated a transgenic mouse line that specifically expresses the rat erbB2 cDNA in the heart under the control of the cardiac-specific ␣-myosin heavy chain promoter. When crossed into the null background, the expression of the rat erbB2 cDNA rescued the cardiac phenotype in the erbB2-null mutant mice that survive until birth but display an absence of Schwann cells and a severe loss of both motor and spinal sensory neurons. To study the role of erbB2 in the adult heart, we generated conditional mutant mice carrying a cardiac-restricted deletion of erbB2. These erbB2 conditional mutants exhibited multiple independent parameters of dilated cardiomyopathy, including chamber dilation, wall thinning, and decreased contractility. Interestingly, treatment of breast cancers overexpressing erbB2 with Herceptin (Trastuzumab), a humanized monoclonal antibody specific to the extracellular domain of erbB2, results in some patients developing cardiac dysfunction. The adverse effect is increased significantly in those patients who also receive the chemotherapeutical agent anthracycline. We found that erbB2-deficient cardiac myocytes are more susceptible to anthracyclineinduced cytotoxicity. These results suggest that erbB2 signaling in the heart is essential for the prevention of dilated cardiomyopathy. These lines of mice provide models with which to elucidate the molecular and cellular mechanisms by which erbB2 signaling regulates cardiac functions. These mice also will provide important information for devising strategies to mitigate the cardiotoxic effects of Herceptin treatment, allowing for the potential expanded use of this drug to treat all cancers overexpressing erbB2.

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“…Localization of Syne-1 in Developing and Denervated Muscles-Synapse-associated myonuclei become transcriptionally specialized by E15, soon after synapses form (30,31), and nuclear clusters form beneath the postsynaptic apparatus soon after birth (32). As a first step in determining whether Syne-1 might be involved in either of these developmental steps, we asked when Syne-1 became associated with synaptic and extrasynaptic nuclei.…”

Section: A Screen For Components Of the Postsynaptic Apparatus-tomentioning

confidence: 99%

Syne-1, A Dystrophin- and Klarsicht-related Protein Associated with Synaptic Nuclei at the Neuromuscular Junction

Apel¹,

Lewis²,

Grady³

et al. 2000

Journal of Biological Chemistry

244

223

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We describe a novel protein, Syne-1, that is associated with nuclear envelopes in skeletal, cardiac, and smooth muscle cells. Syne-1 contains multiple spectrin repeats similar to those found in dystrophin and utrophin, as well as a domain homologous to the carboxyl-terminal of Klarsicht, a protein associated with nuclei and required for a subset of nuclear migrations in Drosophila. In adult skeletal muscle fibers, levels of Syne-1 are highest in the nuclei that lie beneath the postsynaptic membrane at the neuromuscular junction. These nuclei are transcriptionally specialized, expressing genes for synaptic components at higher levels than extrasynaptic nuclei in the same cytoplasm. Syne-1 is the first protein found to be selectively associated with synaptic nuclei. Syne-1 becomes concentrated in synaptic nuclei postnatally. It remains synaptically enriched following denervation or degeneration/regeneration, and is also present at high levels in the central nuclei of dystrophic myotubes. The location and structure of Syne-1 suggest that it may participate in the migration of myonuclei in myotubes and/or their anchoring at the postsynaptic apparatus. Finally, we identify a homologous gene, syne-2, that is expressed in an overlapping but distinct pattern.Skeletal muscle fibers are syncytial; in most mammalian skeletal muscles, each fiber contains several hundred myonuclei. Of these, a few are located beneath the postsynaptic membrane at the neuromuscular junction (NMJ).1 Synaptic nuclei are specialized in several respects. First, multiple nuclei (generally 3-8) are invariably associated with synaptic sites. Because Ͻ1% of the muscle fiber surface is synaptic, one would expect only a minority of synaptic sites to be associated with even a single nucleus if nuclear distribution were random. Second, most nuclei are well separated from their neighbors, but synaptic nuclei occur in tight clusters. Third, synaptic nuclei are larger and rounder than extrasynaptic nuclei (1-3).Finally, synaptic nuclei are transcriptionally specialized; they express genes for several synaptic proteins, including subunits of the acetylcholine receptor (AChR), at levels far higher than those of extrasynaptic nuclei in the same cytoplasm (4 -6). As a result, mRNAs for synaptic proteins are concentrated in synaptic areas, allowing local synthesis of synaptic constituents. This local synthesis has been of considerable interest to neurobiologists, because it contributes to postsynaptic differentiation, and because it may serve as a model for central synapses, in which some components of dendritic spines are thought to be synthesized within the spine itself (7).The formation of the postsynaptic apparatus, including the accumulation and specialization of synaptic nuclei, is controlled by the nerve. One critical nerve-derived signal is the proteoglycan agrin which is required for all aspects of postsynaptic differentiation, including transcriptional specialization of synaptic nuclei (8 -10). A critical component of the agrin receptor is the muscle-sp...

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Compartmentalized Expression of the α- and γ-Subunits of the Acetylcholine Receptor in Recently Fused Myofibers

Cited by 23 publications

References 0 publications

A novel synapse-associated noncoding RNA.

A novel synapse-associated noncoding RNA.

Essential Roles of Her2/erbB2 in Cardiac Development and Function

Syne-1, A Dystrophin- and Klarsicht-related Protein Associated with Synaptic Nuclei at the Neuromuscular Junction

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