RNF220 is required for cerebellum development and regulates medulloblastoma progression through epigenetic modulation of Shh signaling

Ma, Ping; An, Tao; Zhu, Liang; Zhang, Longlong; Wang, Huishan; Ren, Biyu; Sun, Bin; Xiao-fang, Zhou; Mao, Bingyu

doi:10.1242/dev.188078

Cited by 11 publications

(28 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another RNF220 target, Sin3B [ 31 ], is elevated only in RNF220 −/− NSCs, but not in ZC4H2 −/− NSCs ( Figure 6 B and Supplementary Figure S3E,F ). In cerebellar granule neuron progenitors and medulloblastoma cells, RNF220 targets EED for degradation and promotes Shh signaling epigenetically [ 32 ]. However, RNF220 does not interact with EED in NSCs [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Loss of ZC4H2 and RNF220 Inhibits Neural Stem Cell Proliferation and Promotes Neuronal Differentiation

Zhang

Zhu

et al. 2020

Cells

Self Cite

View full text Add to dashboard Cite

The ubiquitin E3 ligase RNF220 and its co-factor ZC4H2 are required for multiple neural developmental processes through different targets, including spinal cord patterning and the development of the cerebellum and the locus coeruleus. Here, we explored the effects of loss of ZC4H2 and RNF220 on the proliferation and differentiation of neural stem cells (NSCs) derived from mouse embryonic cortex. We showed that loss of either ZC4H2 or RNF220 inhibits the proliferation and promotes the differentiation abilities of NSCs in vitro. RNA-Seq profiling revealed 132 and 433 differentially expressed genes in the ZC4H2−/− and RNF220−/− NSCs, compared to wild type (WT) NSCs, respectively. Specifically, Cend1, a key regulator of cell cycle exit and differentiation of neuronal precursors, was found to be upregulated in both ZC4H2−/− and RNF220−/− NSCs at the mRNA and protein levels. The targets of Cend1, such as CyclinD1, Notch1 and Hes1, were downregulated both in ZC4H2−/− and RNF220−/− NSCs, whereas p53 and p21 were elevated. ZC4H2−/− and RNF220−/− NSCs showed G0/G1 phase arrest compared to WT NSCs in cell cycle analysis. These results suggested that ZC4H2 and RNF220 are likely involved in the regulation of neural stem cell proliferation and differentiation through Cend1.

show abstract

Section: Discussionmentioning

confidence: 99%

“…In cerebellar granule neuron progenitors and medulloblastoma cells, RNF220 targets EED for degradation and promotes Shh signaling epigenetically [ 32 ]. However, RNF220 does not interact with EED in NSCs [ 32 ]. Thus, the direct target of ZC4H2/RNF220 involved in Cend1 regulation remains to be explored.…”

Section: Discussionmentioning

confidence: 99%

Loss of ZC4H2 and RNF220 Inhibits Neural Stem Cell Proliferation and Promotes Neuronal Differentiation

Zhang

Zhu

et al. 2020

Cells

Self Cite

View full text Add to dashboard Cite

show abstract

“…Recently, we reported that RNF220 modulates Shh/Gli signaling through targeting Glis for K63-linked polyubiquitination and thus is involved in early neural patterning during vertebrate embryo development ( Ma et al., 2019 ). It is also involved in the development of the cerebellum and the locus coeruleus through targeting EED and Phox2a/b, respectively ( Ma et al., 2020a ; Song et al., 2020 ). In neural stem cells, loss of RNF220 inhibits cell proliferation and promotes cell differentiation in vitro ( Zhang et al., 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Haploinsufficiency of the TDP43 ubiquitin E3 ligase RNF220 leads to ALS-like motor neuron defects in the mouse

Wang

et al. 2021

Journal of Molecular Cell Biology

Self Cite

View full text Add to dashboard Cite

TDP43 pathology is seen in a large majority of amyotrophic lateral sclerosis (ALS) cases, suggesting a central pathogenic role of this regulatory protein. Clarifying the molecular mechanism controlling TDP43 stability and subcellular location might provide important insights into ALS therapy. The ubiquitin E3 ligase RNF220 is involved in different neural developmental processes through various molecular targets in the mouse. Here, we report that the RNF220+/- mice showed progressively decreasing mobility to different extents, some of which developed typical ALS pathological characteristics in spinal motor neurons, including TDP43 cytoplasmic accumulation, atrocytosis, muscle denervation, and atrophy. Mechanistically, RNF220 interacts with TDP43 in vitro and in vivo and promotes its polyubiquitination and proteasomal degradation. In conclusion, we propose that RNF220 might be a modifier of TDP43 function in vivo and contribute to TDP43 pathology in neurodegenerative disease like ALS.

show abstract

“…Whole exome sequencing (WES) performed in 5 large consanguineous nuclear families allowed to identify homozygosity for two recurrent missense variants affecting highly conserved residues of RNF220 as the causative event underlying AR-LAD. RNF220 encodes an evolutionally conserved RING finger E3 ubiquitin ligase 4 highly expressed in developing nervous system where it modulates both ventral spinal cord patterning [5][6][7] and cerebellum development 8 . According with its neuronal expression, RNF220 has recently been involved in the regulation of neural stem cell proliferation and differentiation 9 , and in the development of noradrenergic neurons 10 .…”

Section: Introductionmentioning

confidence: 99%

Biallelic mutations in RNF220 cause laminopathies featuring leukodystrophy, ataxia and deafness

Sferra

Fortugno

Motta

et al. 2021

Brain

View full text Add to dashboard Cite

Leukodystrophies are a heterogeneous group of rare inherited disorders that involve preferentially the white matter of the central nervous system (CNS). These conditions are characterized by a primary glial cell and myelin sheath pathology of variable etiology, which causes secondary axonal degeneration, generally emerging with disease progression. Whole exome sequencing performed in 5 large consanguineous nuclear families allowed to identify homozygosity for two recurrent missense variants affecting highly conserved residues of RNF220 as the causative event underlying a novel form of leukodystrophy with ataxia and sensorineural deafness. We report on two homozygous missense variants (p.R363Q and p.R365Q) in the ubiquitin E3 ligase RNF220 as the cause underlying a novel form of leukodystrophy with ataxia and sensorineural deafness having fibrotic cardiomyopathy and hepatopathy as associated features, in seven consanguineous families. Mass spectrometry analysis identified lamin B1 as RNF220 binding protein and co-immunoprecipitation experiments demonstrated reduced binding of both RNF220 mutants to lamin B1. We demonstrate that RNF220 silencing in Drosophila melanogaster specifically affects proper localization of lamin Dm0, the fly lamin B1 orthologue, promotes its aggregation, and causes a neurodegenerative phenotype, strongly supporting the functional link between RNF220 and lamin B1. Finally, we demonstrate that RNF220 plays a crucial role in the maintenance of nuclear morphology: mutations primary skin fibroblasts determine nuclear abnormalities such as blebs, herniations and invaginations, which are typically observed in cells of patients affected by laminopathies. Overall, our data identify RNF220 as a gene implicated in leukodystrophy with ataxia and sensorineural deafness, and document a critical role of RNF220 in the regulation of nuclear lamina. Our findings provide further evidence on the direct link between nuclear lamina dysfunction and neurodegeneration.

show abstract

RNF220 is required for cerebellum development and regulates medulloblastoma progression through epigenetic modulation of Shh signaling

Cited by 11 publications

References 25 publications

Loss of ZC4H2 and RNF220 Inhibits Neural Stem Cell Proliferation and Promotes Neuronal Differentiation

Loss of ZC4H2 and RNF220 Inhibits Neural Stem Cell Proliferation and Promotes Neuronal Differentiation

Haploinsufficiency of the TDP43 ubiquitin E3 ligase RNF220 leads to ALS-like motor neuron defects in the mouse

Biallelic mutations in RNF220 cause laminopathies featuring leukodystrophy, ataxia and deafness

Contact Info

Product

Resources

About