Netrin-4: Focus on Its Role in Axon Guidance, Tissue Stability, Angiogenesis and Tumors

Dong, Fuxing; Liu, Yaping; Yan, Weixing; Meng, Qiqi; Song, Xueli; Cheng, Bing; Yao, Ruiqin

doi:10.1007/s10571-022-01279-4

Cited by 12 publications

(6 citation statements)

References 167 publications

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“…Under higher magnification, we often observed that axons sending branches to adjacent BTX positive patches on EOM SC-derived myotubes ( Figure 9B , arrows). Of note, there was higher expression of several Netrin and Semaphorin family members reported to promote axon-branching in EOM SCs compared to other muscle-derived SCs cultured in differentiation medium ( Figure 7—source data 2 ; Dent et al, 2004 ; Fukunishi et al, 2011 ; Jeroen Pasterkamp et al, 2003 ; Tang and Kalil, 2005 ; Hayano et al, 2014 ; Dong et al, 2023 ). This milieu, comprised of abundant axon guidance molecules, in combination with the robust self-renewability of satellite cells, may contribute to the relative EOM NMJ resistance in ALS.…”

Section: Resultsmentioning

confidence: 99%

Distinct transcriptomic profile of satellite cells contributes to preservation of neuromuscular junctions in extraocular muscles of ALS mice

Li,

Yi,

et al. 2024

eLife

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Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disorder characterized by progressive weakness of almost all skeletal muscles, whereas extraocular muscles (EOMs) are comparatively spared. While hindlimb and diaphragm muscles of end-stage SOD1G93A (G93A) mice (a familial ALS mouse model) exhibit severe denervation and depletion of Pax7+ satellite cells (SCs), we found that the pool of SCs and the integrity of neuromuscular junctions (NMJs) are maintained in EOMs. In cell sorting profiles, SCs derived from hindlimb and diaphragm muscles of G93A mice exhibit denervation-related activation, whereas SCs from EOMs of G93A mice display spontaneous (non-denervation-related) activation, similar to SCs from wild-type mice. Specifically, cultured EOM SCs contain more abundant transcripts of axon guidance molecules, including Cxcl12, along with more sustainable renewability than the diaphragm and hindlimb counterparts under differentiation pressure. In neuromuscular co-culture assays, AAV-delivery of Cxcl12 to G93A-hindlimb SC-derived myotubes enhances motor neuron axon extension and innervation, recapitulating the innervation capacity of EOM SC-derived myotubes. G93A mice fed with sodium butyrate (NaBu) supplementation exhibited less NMJ loss in hindlimb and diaphragm muscles. Additionally, SCs derived from G93A hindlimb and diaphragm muscles displayed elevated expression of Cxcl12 and improved renewability following NaBu treatment in vitro. Thus, the NaBu-induced transcriptomic changes resembling the patterns of EOM SCs may underlie the beneficial effects observed in G93A mice. More broadly, the distinct transcriptomic profile of EOM SCs may offer novel therapeutic targets to slow progressive neuromuscular functional decay in ALS and provide possible “response biomarkers” in pre-clinical and clinical studies.

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Section: Resultsmentioning

confidence: 99%

Distinct transcriptomic profile of satellite cells contributes to preservation of neuromuscular junctions in extraocular muscles of ALS mice

Li,

Yi,

et al. 2024

eLife

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“…Furthermore, in zoom-in views we constantly observed axons ramify to send projections to adjacent BTX positive patches on EOM SC-derived myotubes ( Figure 9B , arrows), which implicated axon branching during innervation. More than a coincidence, several Netrin and Semaphorin family members reported to promote axon-branching were spotted in the signature gene lists of differentiated EOM SCs ( Figure 7-table supplement 2 ) [53-58]. They may help explain the notably high innervation ratio of EOM SC-derived myotubes.…”

Section: Resultsmentioning

confidence: 99%

“…Under higher magnification, we often observed that axons sending branches to adjacent BTX positive patches on EOM SC-derived myotubes (Figure 9B, arrows). Of note, there was higher expression of several Netrin and Semaphorin family members reported to promote axon-branching in EOM SCs compared to other muscle-derived SCs cultured in differentiation medium (Figure 7-Source Data 2) [62][63][64][65][66][67]. This milieu, comprised of abundant axon guidance molecules, in combination with the robust selfrenewability of satellite cells, may contribute to the relative EOM NMJ resistance in ALS.…”

Section: Aav Mediated Overexpression Of Cxcl12 In Myotubes Promotes M...mentioning

confidence: 99%

Distinct transcriptomic profile of satellite cells contributes to preservation of neuromuscular junctions in extraocular muscles of ALS mice

et al. 2023

Preprint

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Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease that affects all voluntary muscles in the body, leading to paralysis and respiratory failure, while the extraocular muscles (EOMs) are largely spared even at the end-stage of ALS. Through whole-mount muscle imaging, we detected severe denervation along with depletion of Pax7+ satellite cells (SCs) peri-neuromuscular junction (NMJ) in hindlimb and diaphragm muscles of end-stage SOD1G93A mice (a familial ALS mouse model), but not in EOMs. Upon isolating SCs from different muscles using fluorescence activated cell sorting (FACS), the FACS profiles of hindlimb and diaphragm SCs of G93A mice exhibited activation and depletion phenotypes but not in wildtype controls. Importantly, both wildtype and G93A EOM SCs exhibited spontaneous activation behavior without significant differences in abundance. Examination of Pax7+ and Ki67+ cell ratios and RNA-Seq of SCs cultured in growth and differentiation medium revealed that EOM SCs maintained renewability and stemness better than diaphragm and hindlimb counterparts, especially in differentiation-favoring environments. Comparative functional annotation analyses indicate enrichment of axon guidance molecules, such as Cxcl12, in cultured EOM SCs. In neuromuscular coculture experiments, overexpressing Cxcl12 in G93A hindlimb SC-derived myotubes enhanced motor neuron axon extension and improved innervation, partially replicating the multi-innervation property of EOM SC-derived myotubes. The unique SC homeostasis regulation and the production of axon guidance molecules including Cxcl12 may explain the ALS resistant nature of EOMs. Intriguingly, feeding G93A mice with sodium butyrate extended the life span of G93A mice, alleviated NMJ denervation and SCs depletion. Butyrate treatment promoted renewability and stemness of cultured G93A hindlimb and diaphragm SCs, as well as Cxcl12 expression. Thus, butyrate-induced EOM SC-like transcriptomic patterns may contribute to its beneficiary effects observed in G93A mice.

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“…Recent studies have identified neural guidance factor 4 (Netrin‐4/Ntn4) as a crucial regulator of BM stiffness, influencing cancer cell aggressiveness 21 . As a member of the netrins family involved in tissue morphogenesis during nervous system development, Netrin‐4 also holds significance in tumor contexts 22 . Netrin‐4 activated oncogenic pathways, such as PI3K/Akt, driving gastric cancer proliferation and invasion through binding with the Neogenin receptor 23 .…”

Section: Introductionmentioning

confidence: 99%

“…21 As a member of the netrins family involved in tissue morphogenesis during nervous system development, Netrin-4 also holds significance in tumor contexts. 22 Netrin-4 activated oncogenic pathways, such as PI3K/Akt, driving gastric cancer proliferation and invasion through binding with the Neogenin receptor. 23 It also downregulated N-cadherin and vimentin, curbing the migratory and invasive potential of breast cancer cells.…”

Section: Introductionmentioning

confidence: 99%

IGF2BP2 inhibits invasion and migration of clear cell renal cell carcinoma via targeting Netrin‐4 in an m⁶A‐dependent manner

Wang,

Zhuang,

Zhen

et al. 2024

Molecular Carcinogenesis

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Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell carcinoma, often leads to a poor prognosis due to metastasis. The investigation of N6‐methyladenosine (m6A) methylation, a crucial RNA modification, and its role in ccRCC, particularly through the m6A reader insulin‐like growth factor 2 mRNA‐binding protein 2 (IGF2BP2), revealed significant insights. We found that IGF2BP2 was notably downregulated in ccRCC, which correlated with tumor aggressiveness and poor prognosis. Thus, IGFBP2 has emerged as an independent prognostic factor of ccRCC. Moreover, a strong positive correlation was observed between the expression of IGF2BP2 and Netrin‐4. Netrin‐4 was also downregulated in ccRCC, and its lower levels were associated with increased malignancy and poor prognosis. Overexpression of IGF2BP2 and Netrin‐4 suppressed the invasion and migration of ccRCC cells, while Netrin‐4 knockdown reversed these effects in ccRCC cell lines. RNA immunoprecipitation (RIP)‐quantitative polymerase chain reaction validated the robust enrichment of Netrin‐4 mRNA in anti‐IGF2BP2 antibody immunoprecipitates. MeRlP showed significantly increased Netrin4 m6A levels after lGF2BP2 overexpression. Moreover, we found that IGF2BP2 recognized and bound to the m6A site within the coding sequence of Netrin‐4, enhancing its mRNA stability. Collectively, these results showed that IGF2BP2 plays a suppressive role in the invasion and migration of ccRCC cells by targeting Netrin‐4 in an m6A‐dependent manner. These findings underscore the potential of IGF2BP2/Netrin‐4 as a promising prognostic biomarker and therapeutic target in patients with ccRCC metastasis.

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Netrin-4: Focus on Its Role in Axon Guidance, Tissue Stability, Angiogenesis and Tumors

Cited by 12 publications

References 167 publications

Distinct transcriptomic profile of satellite cells contributes to preservation of neuromuscular junctions in extraocular muscles of ALS mice

Distinct transcriptomic profile of satellite cells contributes to preservation of neuromuscular junctions in extraocular muscles of ALS mice

Distinct transcriptomic profile of satellite cells contributes to preservation of neuromuscular junctions in extraocular muscles of ALS mice

IGF2BP2 inhibits invasion and migration of clear cell renal cell carcinoma via targeting Netrin‐4 in an m⁶A‐dependent manner

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Netrin-4: Focus on Its Role in Axon Guidance, Tissue Stability, Angiogenesis and Tumors

Cited by 12 publications

References 167 publications

Distinct transcriptomic profile of satellite cells contributes to preservation of neuromuscular junctions in extraocular muscles of ALS mice

Distinct transcriptomic profile of satellite cells contributes to preservation of neuromuscular junctions in extraocular muscles of ALS mice

Distinct transcriptomic profile of satellite cells contributes to preservation of neuromuscular junctions in extraocular muscles of ALS mice

IGF2BP2 inhibits invasion and migration of clear cell renal cell carcinoma via targeting Netrin‐4 in an m6A‐dependent manner

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IGF2BP2 inhibits invasion and migration of clear cell renal cell carcinoma via targeting Netrin‐4 in an m⁶A‐dependent manner