Damage-Induced Neuronal Endopeptidase Is Critical for Presynaptic Formation of Neuromuscular Junctions

Nagata, Kenichi; Kiryu‐Seo, Sumiko; Maeda, Masayuki; Yoshida, Kayo; Morita, Takashi; Kiyama, Hiroshi

doi:10.1523/jneurosci.4521-09.2010

Cited by 36 publications

(45 citation statements)

References 33 publications

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“…Conversely, intercostal muscles were not detectably affected in Clipr-59 −/− embryos at E18.5. Similar differences in defect severity between phrenic and intercostal innervation were also observed in ErbB2- (Lin et al, 2000) and in DINE-deficient mice (Nagata et al, 2010), which could suggest that the deeper the final motor branches are into a muscle, the more severely affected the muscle innervation is. Another hypothesis is that CLIPR-59 deficiency differentially affects motor innervation according to the skeletal muscle type, such that DeSyn muscle (i.e.…”

Section: Research Articlesupporting

confidence: 63%

CLIPR-59: a protein essential for neuromuscular junction stability during mouse late embryonic development

et al. 2013

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CLIPR-59 is a new member of the cytoplasmic linker proteins (CLIP) family mainly localized to the trans-Golgi network. We show here that Clipr-59 expression in mice is restricted to specific pools of neurons, in particular motoneurons (MNs), and progressively increases from embryonic day 12.5 (E12.5) until the first postnatal days. We generated a Clipr-59 knockout mouse model that presents perinatal lethality due to respiratory defects. Physiological experiments revealed that this altered innervation prevents the normal nerve-elicited contraction of the mutant diaphragm that is reduced both in amplitude and fatigue-resistance at E18.5, despite unaffected functional muscular contractility. Innervation of the mutant diaphragm is not altered until E15.5, but is then partially lost in the most distal parts of the muscle. Ultrastructural observations of neuromuscular junctions (NMJs) in the distal region of the diaphragm reveal a normal organization, but a lower density of nerve terminals capped by terminal Schwann cells in E18.5 mutant when compared with control embryos. Similar defects in NMJ stability, with a hierarchy of severity along the caudo-rostral axis, are also observed in other muscles innervated by facial and spinal MNs in Clipr-59 mutant mice. Clipr-59 deficiency therefore affects axon maintenance but not axon guidance toward muscle targets. Thus, CLIPR-59 is involved in the stabilization of specific motor axons at the NMJ during mouse late embryogenesis and its role is crucial for mouse perinatal development.

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Section: Research Articlesupporting

confidence: 63%

CLIPR-59: a protein essential for neuromuscular junction stability during mouse late embryonic development

et al. 2013

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“…From these expression profiles, DINE is expected to function in some subsets of neuronal cells during neuronal development and nerve regeneration. Indeed, previous gene disruption studies, including ours, show that DINE/ECEL1-deficient mice die immediately after birth due to respiratory failure [21,26]. In our previous study, the cause of respiratory failure was determined to be diaphragm atrophy as a result of motor nerve arborization deficiency, showing that DINE deficiency primarily affects muscle innervation [21].…”

Section: Introductionmentioning

confidence: 61%

“…Animals DINE-deficient mice [21] and newly generated DINE knock-in mice (see below for the detailed information) were used in this study. The homozygous mutant mice were obtained by intercrossing the heterozygous parents.…”

Section: Methodsmentioning

confidence: 99%

“…DINE is significantly upregulated in injured neurons in the CNS and PNS in response to various neuronal injuries [14,17,22]. Additionally, DINE is specifically expressed in certain neuronal cells from early embryonic stages [20,21]. From these expression profiles, DINE is expected to function in some subsets of neuronal cells during neuronal development and nerve regeneration.…”

Section: Introductionmentioning

confidence: 99%

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ECEL1 mutation implicates impaired axonal arborization of motor nerves in the pathogenesis of distal arthrogryposis

et al. 2016

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The membrane-bound metalloprotease endothelin-converting enzyme-like 1 (ECEL1) has been newly identified as a causal gene of a specific type of distal arthrogryposis (DA). In contrast to most causal genes of DA, ECEL1 is predominantly expressed in neuronal cells, suggesting a unique neurogenic pathogenesis in a subset of DA patients with ECEL1 mutation. The present study analyzed developmental motor innervation and neuromuscular junction formation in limbs of the rodent homologue damage-induced neuronal endopeptidase (DINE)-deficient mouse. Whole-mount immunostaining was performed in DINE-deficient limbs expressing motoneuron-specific GFP to visualize motor innervation throughout the limb. Although DINE-deficient motor nerves displayed normal trajectory patterns from the spinal cord to skeletal muscles, they indicated impaired axonal arborization in skeletal muscles in the forelimbs and hindlimbs. Systematic examination of motor innervation in over 10 different hindlimb muscles provided evidence that DINE gene disruption leads to insufficient arborization of motor nerves after arriving at the skeletal muscle. Interestingly, the axonal arborization defect in foot muscles appeared more severe than in other hindlimb muscles, which was partially consistent with the proximal-distal phenotypic discordance observed in DA patients. Additionally, the number of innervated neuromuscular junction was significantly reduced in the severely affected DINE-deficient muscle. Furthermore, we generated a DINE knock-in (KI) mouse model with a pathogenic mutation, which was recently identified in DA patients. Axonal arborization defects were clearly detected in motor nerves of the DINE KI limb, which was identical to the DINE-deficient limb. Given that the encoded sequences, as well as ECEL1 and DINE expression profiles, are highly conserved between mouse and human, abnormal arborization of motor axons and subsequent failure of NMJ formation could be a primary cause of DA with ECEL1 mutation.

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“…ns, not statistically different; **P < 0.01; ***P < 0.001; Mann-Whitney test. Ecel1 (also called DINE, or damage-induced neuronal endopeptidase) is required for the proper intramuscular axonal branching of motor neurons in skeletal muscle during embryogenesis (23,24). These results suggest that mutations in neuronally expressed genes such as PIEZO2 and ECEL1, as well as in the already known DA genes that are expressed in muscle, can perturb the neuromuscular pathway that controls the development of muscle tone during embryogenesis.…”

Section: Resultsmentioning

confidence: 95%

Gain-of-function mutations in the mechanically activated ion channel PIEZO2 cause a subtype of Distal Arthrogryposis

Coste

Houge

Murray

et al. 2013

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

202

193

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Mechanotransduction, the pathway by which mechanical forces are translated to biological signals, plays important but poorly characterized roles in physiology. PIEZOs are recently identified, widely expressed, mechanically activated ion channels that are hypothesized to play a role in mechanotransduction in mammals. Here, we describe two distinct PIEZO2 mutations in patients with a subtype of Distal Arthrogryposis Type 5 characterized by generalized autosomal dominant contractures with limited eye movements, restrictive lung disease, and variable absence of cruciate knee ligaments. Electrophysiological studies reveal that the two PIEZO2 mutations affect biophysical properties related to channel inactivation: both E2727del and I802F mutations cause the PIEZO2-dependent, mechanically activated currents to recover faster from inactivation, while E2727del also causes a slowing of inactivation. Both types of changes in kinetics result in increased channel activity in response to a given mechanical stimulus, suggesting that Distal Arthrogryposis Type 5 can be caused by gain-of-function mutations in PIEZO2. We further show that overexpression of mutated PIEZO2 cDNAs does not cause constitutive activity or toxicity to cells, indicating that the observed phenotype is likely due to a mechanotransduction defect. Our studies identify a type of channelopathy and link the dysfunction of mechanically activated ion channels to developmental malformations and joint contractures.congenital contractures | neuromuscular system | whole exome sequencing | whole genome sequencing

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Damage-Induced Neuronal Endopeptidase Is Critical for Presynaptic Formation of Neuromuscular Junctions

Cited by 36 publications

References 33 publications

CLIPR-59: a protein essential for neuromuscular junction stability during mouse late embryonic development

CLIPR-59: a protein essential for neuromuscular junction stability during mouse late embryonic development

ECEL1 mutation implicates impaired axonal arborization of motor nerves in the pathogenesis of distal arthrogryposis

Gain-of-function mutations in the mechanically activated ion channel PIEZO2 cause a subtype of Distal Arthrogryposis

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