“…Some transcripts that were upregulated in SOD1 G93A axons appear detrimental, including Adgr1 (Zuko et al., 2016) (Figure 5E). In addition, upregulation of some transcripts in ALS could reflect compensatory mechanisms preventing axon damage or dysfunction in SOD1 G93A axons, including Dhx36 (Bicker et al., 2013), the ALS-causative gene Nek1 (Kenna et al., 2016), F3 (Bizzoca et al., 2009), Rbpms (Hornberg et al., 2013), and Farp1 (Zhuang et al., 2009) (Figure 5E).Figure 5Overexpression of SOD1 G93A Induces Changes in the Axonal Transcriptome(A) Staining for SOD1 and misfolded SOD1 in MN cultures. In SOD1 G93A -expressing cells high levels of both SOD1 and misfSOD1 are detected, whereas no misfSOD1 is detected in control cells.(B and C) (C) Mouse Sod1 is enriched in axons, while (B) transgenic human SOD1 is equally divided over both compartments.…”
Section: Resultsmentioning
confidence: 99%
“…Interestingly, the SOD1 mutation caused an upregulation of transcripts that could be beneficial to axons, possibly through compensatory mechanisms aimed at preventing axon damage or dysfunction. These transcripts with potential beneficial properties included Dhx36 , an ATP-dependent helicase, which mediates dendritic localization of miR-134, affecting synaptic protein synthesis and plasticity (Bicker et al., 2013); F3 , a cell adhesion molecule involved in neurite outgrowth (Bizzoca et al., 2009); Rbpms , an RNA-binding protein with importance for RNA-granule localization and dendritic tree complexity (Hornberg et al., 2013); Farp1 , a marker for LMC MNs that positively regulates dendrite growth (Zhuang et al., 2009); and Nek1 , which has a putative role in microtubule stability, neuronal morphology, and axon polarity. Interestingly, loss-of-function variants of NEK1 confer susceptibility to ALS in humans (Kenna et al., 2016).…”
SummarySpinal motor axons traverse large distances to innervate target muscles, thus requiring local control of cellular events for proper functioning. To interrogate axon-specific processes we developed Axon-seq, a refined method incorporating microfluidics, RNA sequencing (RNA-seq), and bioinformatic quality control. We show that the axonal transcriptome is distinct from that of somas and contains fewer genes. We identified 3,500–5,000 transcripts in mouse and human stem cell-derived spinal motor axons, most of which are required for oxidative energy production and ribogenesis. Axons contained transcription factor mRNAs, e.g., Ybx1, with implications for local functions. As motor axons degenerate in amyotrophic lateral sclerosis (ALS), we investigated their response to the SOD1G93A mutation, identifying 121 ALS-dysregulated transcripts. Several of these are implicated in axonal function, including Nrp1, Dbn1, and Nek1, a known ALS-causing gene. In conclusion, Axon-seq provides an improved method for RNA-seq of axons, increasing our understanding of peripheral axon biology and identifying therapeutic targets in motor neuron disease.
“…Some transcripts that were upregulated in SOD1 G93A axons appear detrimental, including Adgr1 (Zuko et al., 2016) (Figure 5E). In addition, upregulation of some transcripts in ALS could reflect compensatory mechanisms preventing axon damage or dysfunction in SOD1 G93A axons, including Dhx36 (Bicker et al., 2013), the ALS-causative gene Nek1 (Kenna et al., 2016), F3 (Bizzoca et al., 2009), Rbpms (Hornberg et al., 2013), and Farp1 (Zhuang et al., 2009) (Figure 5E).Figure 5Overexpression of SOD1 G93A Induces Changes in the Axonal Transcriptome(A) Staining for SOD1 and misfolded SOD1 in MN cultures. In SOD1 G93A -expressing cells high levels of both SOD1 and misfSOD1 are detected, whereas no misfSOD1 is detected in control cells.(B and C) (C) Mouse Sod1 is enriched in axons, while (B) transgenic human SOD1 is equally divided over both compartments.…”
Section: Resultsmentioning
confidence: 99%
“…Interestingly, the SOD1 mutation caused an upregulation of transcripts that could be beneficial to axons, possibly through compensatory mechanisms aimed at preventing axon damage or dysfunction. These transcripts with potential beneficial properties included Dhx36 , an ATP-dependent helicase, which mediates dendritic localization of miR-134, affecting synaptic protein synthesis and plasticity (Bicker et al., 2013); F3 , a cell adhesion molecule involved in neurite outgrowth (Bizzoca et al., 2009); Rbpms , an RNA-binding protein with importance for RNA-granule localization and dendritic tree complexity (Hornberg et al., 2013); Farp1 , a marker for LMC MNs that positively regulates dendrite growth (Zhuang et al., 2009); and Nek1 , which has a putative role in microtubule stability, neuronal morphology, and axon polarity. Interestingly, loss-of-function variants of NEK1 confer susceptibility to ALS in humans (Kenna et al., 2016).…”
SummarySpinal motor axons traverse large distances to innervate target muscles, thus requiring local control of cellular events for proper functioning. To interrogate axon-specific processes we developed Axon-seq, a refined method incorporating microfluidics, RNA sequencing (RNA-seq), and bioinformatic quality control. We show that the axonal transcriptome is distinct from that of somas and contains fewer genes. We identified 3,500–5,000 transcripts in mouse and human stem cell-derived spinal motor axons, most of which are required for oxidative energy production and ribogenesis. Axons contained transcription factor mRNAs, e.g., Ybx1, with implications for local functions. As motor axons degenerate in amyotrophic lateral sclerosis (ALS), we investigated their response to the SOD1G93A mutation, identifying 121 ALS-dysregulated transcripts. Several of these are implicated in axonal function, including Nrp1, Dbn1, and Nek1, a known ALS-causing gene. In conclusion, Axon-seq provides an improved method for RNA-seq of axons, increasing our understanding of peripheral axon biology and identifying therapeutic targets in motor neuron disease.
“…The various functions played by IGSF‐CAMs depend on the tight spatiotemporal control of their cellular and subcellular localization during development. In the cerebellum, for example, F3/contactin undergoes sharp changes in its cellular distribution, concomitant with neuronal differentiation (Bizzoca et al, ). To gain further insight into the role of IgSF3 during brain development, we performed a detailed analysis of its cellular and subcellular localization in the mouse cerebellum at P0 and P7.…”
“…CNTN1 is mostly expressed in the human brain and neuronal tissues and is limitedly expressed in other tissues. CNTN1 primarily functions as an axonal glycoprotein important in the facilitation of axonal growth and the outgrowth of neurites [ 10 , 11 ], but also plays important roles in other neuronal developmental processes, such as differentiation and development of glial cells, myelination, synaptogenesis, and fasciculation [ 11 , 12 , 13 , 14 ]. The CNTN1 knockout transgenic mice shows a cerebellar phenotype in which the parallel fibers of the granule cell neurons are misoriented, concurrent with a 25% reduction on cerebellar volume, supporting its importance in axon guidance [ 15 ].…”
Section: The Role Of Cntn1 In Neuronal Developmentmentioning
Even with recent progress, cancer remains the second leading cause of death, outlining a need to widen the current understanding on oncogenic factors. Accumulating evidence from recent years suggest Contactin 1 (CNTN1)’s possession of multiple oncogenic activities in a variety of cancer types. CNTN1 is a cell adhesion molecule that is dysregulated in many human carcinomas and plays important roles in cancer progression and metastases. Abnormalities in CNTN1 expression associate with cancer progression and poor prognosis. Mechanistically, CNTN1 functions in various signaling pathways frequently altered in cancer, such as the vascular endothelial growth factor C (VEGFC)-VEGF receptor 3 (VEFGR3)/fms-related tyrosine kinase 4 (Flt4) axis, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), Notch signaling pathway and epithelial-mesenchymal transition (EMT) process. These oncogenic events are resulted via interactions between tumor and stroma, which can be contributed by CNTN1, an adhesion protein. CNTN1 expression in breast cancer correlates with the expression of genes functioning in cancer-stroma interactions and skeletal system development. Evidence supports that CNTN1 promotes cancer-stromal interaction, resulting in activation of a complex network required for cancer progression and metastasis (bone metastasis for breast cancer). CNTN1 inhibitions has been proven to be effective in experimental models to reduce oncogenesis. In this paper, we will review CNTN1′s alterations in cancer, its main biochemical mechanisms and interactions with its relevant cancer pathways.
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