Maintenance of Acetylcholine Receptor Number by Neuregulins at the Neuromuscular Junction in Vivo

Sandrock, Alfred; Dryer, Stuart E.; Rosen, Kenneth M.; Gozani, Shai N.; Kramer, Rainer; Theill, Lars E.; Fischbach, Gerald D.

doi:10.1126/science.276.5312.599

Cited by 254 publications

(186 citation statements)

References 42 publications

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“…The distributions and biological activities of these isoforms do not completely overlap (5,11,12). However, there is strong evidence that Ig-containing and cysteine-rich isoforms are both important for synapse formation and maintenance at the mouse neuromuscular junction (4,12). In the present experiments, we used antibodies and riboprobes directed against the EGF-like domain, and consequently, we cannot state which isoforms are essential.…”

Section: Discussionmentioning

confidence: 89%

“…Of these two groups, the ␤-neuregulin-1 (␤-NEU1) isoforms are considerably more potent in neural systems and have diverse functions in neural development. These include regulation of nicotinic ACh receptor expression in peripheral targets (3)(4)(5) and regulation of N-methyl-D-aspartate (6) and ␥-aminobutyric acid type A (7) receptors in the cerebellum. In addition, ␤-neuregulins regulate proliferation and differentiation of glial and Schwann cells (8,9), neuronal migration (10), cell number, and brain morphogenetic pattern (2,11,12).…”

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confidence: 99%

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β-Neuregulin-1 is required for the in vivo development of functional Ca ²⁺ -activated K ⁺ channels in parasympathetic neurons

Cameron

Dryer

2001

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

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The development of functional Ca 2؉ -activated K ؉ channels (KCa) in chick ciliary ganglion (CG) neurons requires interactions with afferent preganglionic nerve terminals. Here we show that the essential preganglionic differentiation factor is an isoform of ␤-neuregulin-1. ␤-Neuregulin-1 transcripts are expressed in the midbrain preganglionic Edinger-Westphal nucleus at developmental stages that coincide with or precede the normal onset of macroscopic K Ca in CG neurons. Injection of ␤-neuregulin-1 peptide into the brains of developing embryos evoked a robust stimulation of functional KCa channels at stages before the normal appearance of these channels in CG neurons developing in vivo. Conversely, injection of a neutralizing antiserum specific for ␤-neuregulin-1 inhibited the development of KCa channels in CG neurons. Low concentrations of ␤-neuregulin-1 evoked a robust increase in whole-cell KCa in CG neurons cocultured with iris target tissues. By contrast, culturing CG neurons with iris cells or low concentrations of ␤-neuregulin-1 by themselves was insufficient to stimulate KCa. These data suggest that the preganglionic factor required for the development of K Ca in ciliary ganglion neurons is an isoform of ␤-neuregulin-1, and that this factor acts in concert with targetderived trophic molecules to regulate the differentiation of excitability.ciliary ganglion ͉ slowpoke ͉ trophic factor ͉ neuregulins ͉ transforming growth factor ␤

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Section: Discussionmentioning

confidence: 89%

mentioning

confidence: 99%

β-Neuregulin-1 is required for the in vivo development of functional Ca ²⁺ -activated K ⁺ channels in parasympathetic neurons

Cameron

Dryer

2001

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

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“…Some molecular factors support such adjustments (3,4) and some physiological mechanisms have been proposed, such as changes in postsynaptic receptor composition (5,6). Work at the neuromuscular junction has uncovered other forms of synaptic homeostasis whereby purely postsynaptic interventions cause alterations in presynaptic function (3,4,7,8). However, no clear picture has emerged of the underlying molecular mechanisms that control presynaptic homeostasis.…”

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confidence: 99%

Presynaptic homeostasis at CNS nerve terminals compensates for lack of a key Ca ²⁺ entry pathway

Piedras-Renterı́a

Pyle

Diehn

et al. 2004

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

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At central synapses, P͞Q-type Ca 2؉ channels normally provide a critical Ca 2؉ entry pathway for neurotransmission. Nevertheless, we found that nerve terminals lacking ␣1A (CaV2.1), the pore-forming subunit of P͞Q-type channels, displayed a remarkable preservation of synaptic function. Two consistent physiological changes reflective of synaptic homeostasis were observed in cultured hippocampal neurons derived from ␣1A (؊/؊) mice. First, the presynaptic response to an ionophore-mediated Ca 2؉ elevation was 50% greater, indicating an enhanced Ca 2؉ sensitivity of the release machinery. Second, basal miniature excitatory postsynaptic current frequency in ␣1A (؊/؊) neurons was increased 2-fold compared with WT neurons and occluded the normal response of presynaptic terminals to cAMP elevation, suggesting that the compensatory mechanism in ␣1A (؊/؊) synapses and the modulation of presynaptic function by PKA might share a final common pathway. We used cDNA microarray analysis to identify molecular changes underlying homeostatic regulation in the ␣1A (؊/؊) hippocampus. The 40,000 entries in our custom-made array included likely targets of presynaptic homeostasis, along with many other transcripts, allowing a wide-ranging examination of gene expression. The developmental pattern of changes in transcript levels relative to WT was striking; mRNAs at 5 and 11 days postnatal showed little deviation, but clear differences emerged by 22 days. Many of the transcripts that differed significantly in abundance corresponded to known genes that could be incorporated within a logical pattern consistent with the modulation of presynaptic function. Changes in endocytotic proteins, signal transduction kinases, and candidates for Ca 2؉ -sensing molecules were consistent with implications of the direct physiological experiments.

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“…The number of postsynaptic acetylcholine receptors is reduced in heterozygous NRG knockout (NRGϩ/Ϫ) mice (11). Homozygous knockout mice (NRGϪ/Ϫ) die by embryonic day 10 before neuromuscular junction develops (12,13).…”

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confidence: 99%

The Release of Acetylcholine Receptor Inducing Activity (ARIA) from Its Transmembrane Precursor in Transfected Fibroblasts

Han¹,

Fischbach

1999

Journal of Biological Chemistry

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Acetylcholine receptor inducing activity (ARIA) is made by motoneurons and is released at the neuromuscular synapse to stimulate the synthesis of acetylcholine receptors by skeletal muscle. ARIA is derived from a transmembrane precursor (pro-ARIA) via proteolytic cleavage of the ectodomain. We studied requirements in the amino acid sequence at the cleavage site with various substitution and deletion mutations. Wild type (WT) and mutant proteins were transiently expressed in COS cells, and release of ARIA into the conditioned medium was measured by tyrosine phosphorylation of its receptor, p185, in L6 cells. Removal of all potential cleavage sites between the extracellular epidermal growth factor domain and the transmembrane domain by substitution and small deletions (<11 amino acid residues out of 21) did not significantly reduce ARIA release, whereas larger deletions abolished it. We propose that cleavage occurs independently of amino acid sequence at a short distance from the epidermal growth factor domain, unless sterically hindered by the nearby secondary structure. A mutant with shorter cytoplasmic domain ("c" isoform) released significantly less ARIA than the WT ("a" isoform), suggesting that the c isoform may be suitable for signaling through direct cell-cell contact. Alternatively, proteolytic conversion of the a isoform to the c isoform may rapidly down-regulate release of ARIA.

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Maintenance of Acetylcholine Receptor Number by Neuregulins at the Neuromuscular Junction in Vivo

Cited by 254 publications

References 42 publications

β-Neuregulin-1 is required for the in vivo development of functional Ca ²⁺ -activated K ⁺ channels in parasympathetic neurons

β-Neuregulin-1 is required for the in vivo development of functional Ca ²⁺ -activated K ⁺ channels in parasympathetic neurons

Presynaptic homeostasis at CNS nerve terminals compensates for lack of a key Ca ²⁺ entry pathway

The Release of Acetylcholine Receptor Inducing Activity (ARIA) from Its Transmembrane Precursor in Transfected Fibroblasts

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Maintenance of Acetylcholine Receptor Number by Neuregulins at the Neuromuscular Junction in Vivo

Cited by 254 publications

References 42 publications

β-Neuregulin-1 is required for the in vivo development of functional Ca 2+ -activated K + channels in parasympathetic neurons

β-Neuregulin-1 is required for the in vivo development of functional Ca 2+ -activated K + channels in parasympathetic neurons

Presynaptic homeostasis at CNS nerve terminals compensates for lack of a key Ca 2+ entry pathway

The Release of Acetylcholine Receptor Inducing Activity (ARIA) from Its Transmembrane Precursor in Transfected Fibroblasts

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β-Neuregulin-1 is required for the in vivo development of functional Ca ²⁺ -activated K ⁺ channels in parasympathetic neurons

β-Neuregulin-1 is required for the in vivo development of functional Ca ²⁺ -activated K ⁺ channels in parasympathetic neurons

Presynaptic homeostasis at CNS nerve terminals compensates for lack of a key Ca ²⁺ entry pathway