Role of Nav1.9 in activity-dependent axon growth in motoneurons

Subramanian, Narayan; Wetzel, Andrea; Dombert, Benjamin; Yadav, Preeti; Havlicek, Steven; Jablonka, Sibylle; Nassar, Mohammed A.; Blum, Robert; Sendtner, Michael

doi:10.1093/hmg/dds195

Cited by 43 publications

(74 citation statements)

References 64 publications

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“…Isolation of total RNA, reverse transcription and quantitative real-time polymerase chain reaction (qRT-PCR) were performed as previously described with few changes (57). Total RNA from primary cultured mouse kidney cells and mouse kidney tissue was isolated and purified with the RNeasy Mini Kit (QIAGEN).…”

Section: Methodsmentioning

confidence: 99%

“…Oligo 6.0 software (MedProbe) served as program to select intron-spanning primers targeting the mus musculus cathepsin D g ene (NM_009983.2; 330-forward 5′-GCCGCAGTGTTTCACAG-3′; 479-reverse 5′-TGAGCCGTAGTGGATGTCAA-3′; amplification product: 169 bp). Optimized primers for the two housekeeping reference genes, GAPDH and β-actin, have been used as published earlier (57): GAPDH: NM_008084; 205-forward 5′-GCAAATTCAACGGCACA-3′; 337-reverse 5′-CACCAGTAGACTCCACGAC-3′; amplification product: 141 bp; β-actin: NM_007393; forward 5′-GCCAACCGTGAAAAGATGAC-3′; reverse 5′-GGCGTGAGGGAGAGCATAG-3′. In order to verify the specificity of the PCR products gel electrophoresis, melting curve analysis and ‘-RT’ (reverse transcriptase) as well as water control PCR reactions were conducted.…”

Section: Methodsmentioning

confidence: 99%

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Proteomic analysis reveals co-ordinated alterations in protein synthesis and degradation pathways in LRRK2 knockout mice

Pellegrini

Hauser

et al. 2018

Human Molecular Genetics

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Mutations in leucine-rich repeat kinase 2 (LRRK2) segregate with familial Parkinson’s disease (PD) and genetic variation around LRRK2 contributes to risk of sporadic disease. Although knockout (KO) of Lrrk2 or knock-in of pathogenic mutations into the mouse germline does not result in a PD phenotype, several defects have been reported in the kidneys of Lrrk2 KO mice. To understand LRRK2 function in vivo, we used an unbiased approach to determine which protein pathways are affected in LRRK2 KO kidneys. We nominated changes in cytoskeletal-associated proteins, lysosomal proteases, proteins involved in vesicular trafficking and in control of protein translation. Changes were not seen in mice expressing the pathogenic G2019S LRRK2 mutation. Using cultured epithelial kidney cells, we replicated the accumulation of lysosomal proteases and demonstrated changes in subcellular distribution of the cation-independent mannose-6-phosphate receptor. These results show that loss of LRRK2 leads to co-ordinated responses in protein translation and trafficking and argue against a dominant negative role for the G2019S mutation.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Proteomic analysis reveals co-ordinated alterations in protein synthesis and degradation pathways in LRRK2 knockout mice

Pellegrini

Hauser

et al. 2018

Human Molecular Genetics

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“…Muscular weakness in the affected individuals might be attributed to a developmental role of the channel in motor neurons, as Na v 1.9 was shown to contribute to the spontaneous neural activity that promotes axon growth in these neurons 33,34 . Prominent hyperhidrosis and gastrointestinal malfunction in the affected individuals may be a consequence of autonomic dysfunction.…”

Section: Scn11amentioning

confidence: 99%

A de novo gain-of-function mutation in SCN11A causes loss of pain perception

et al. 2013

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The sensation of pain protects the body from serious injury. Using exome sequencing, we identified a specific de novo missense mutation in SCN11A in individuals with the congenital inability to experience pain who suffer from recurrent tissue damage and severe mutilations. Heterozygous knock-in mice carrying the orthologous mutation showed reduced sensitivity to pain and self-inflicted tissue lesions, recapitulating aspects of the human phenotype. SCN11A encodes Nav1.9, a voltage-gated sodium ion channel that is primarily expressed in nociceptors, which function as key relay stations for the electrical transmission of pain signals from the periphery to the central nervous system. Mutant Nav1.9 channels displayed excessive activity at resting voltages, causing sustained depolarization of nociceptors, impaired generation of action potentials and aberrant synaptic transmission. The gain-of-function mechanism that underlies this channelopathy suggests an alternative way to modulate pain perception.

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“…For knockdown of Smn, an Smn (5 ′ -GAAGAATGCCACAACTCCC -3 ′ ) shRNA sequence (Zhang et al 2008) was cloned into the pSIH-H1 shRNA vector (System Bioscience) and HEK293T cells were used to generate viruses as described previously (Lois et al 2002; Smn deficiency alters the axonal transcriptome www.rnajournal.org 1799 Subramanian et al 2012). Lentiviral knockdown experiments were performed by incubation of motoneurons before plating with either knockdown or control viruses containing empty pSIH-H1 for 10 min at room temperature.…”

Section: Knockdown Of Smn Via Lentiviral Shrna In Embryonic Motoneuronsmentioning

confidence: 99%

Subcellular transcriptome alterations in a cell culture model of spinal muscular atrophy point to widespread defects in axonal growth and presynaptic differentiation

Saal

Briese

Kneitz

et al. 2014

RNA

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Neuronal function critically depends on coordinated subcellular distribution of mRNAs. Disturbed mRNA processing and axonal transport has been found in spinal muscular atrophy and could be causative for dysfunction and degeneration of motoneurons. Despite the advances made in characterizing the transport mechanisms of several axonal mRNAs, an unbiased approach to identify the axonal repertoire of mRNAs in healthy and degenerating motoneurons has been lacking. Here we used compartmentalized microfluidic chambers to investigate the somatodendritic and axonal mRNA content of cultured motoneurons by microarray analysis. In axons, transcripts related to protein synthesis and energy production were enriched relative to the somatodendritic compartment. Knockdown of Smn, the protein deficient in spinal muscular atrophy, produced a large number of transcript alterations in both compartments. Transcripts related to immune functions, including MHC class I genes, and with roles in RNA splicing were up-regulated in the somatodendritic compartment. On the axonal side, transcripts associated with axon growth and synaptic activity were down-regulated. These alterations provide evidence that subcellular localization of transcripts with axonal functions as well as regulation of specific transcripts with nonautonomous functions is disturbed in Smn-deficient motoneurons, most likely contributing to the pathophysiology of spinal muscular atrophy.

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Role of Nav1.9 in activity-dependent axon growth in motoneurons

Cited by 43 publications

References 64 publications

Proteomic analysis reveals co-ordinated alterations in protein synthesis and degradation pathways in LRRK2 knockout mice

Proteomic analysis reveals co-ordinated alterations in protein synthesis and degradation pathways in LRRK2 knockout mice

A de novo gain-of-function mutation in SCN11A causes loss of pain perception

Subcellular transcriptome alterations in a cell culture model of spinal muscular atrophy point to widespread defects in axonal growth and presynaptic differentiation

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