scholarly journals FMRP and MOV10 regulate Dicer1 expression and dendrite development

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0260005
Author(s):  
Monica C. Lannom ◽  
Joshua Nielsen ◽  
Aatiqa Nawaz ◽  
Temirlan Shilikbay ◽  
Stephanie Ceman

Fragile X syndrome results from the loss of expression of the Fragile X Mental Retardation Protein (FMRP). FMRP and RNA helicase Moloney Leukemia virus 10 (MOV10) are important Argonaute (AGO) cofactors for miRNA-mediated translation regulation. We previously showed that MOV10 functionally associates with FMRP. Here we quantify the effect of reduced MOV10 and FMRP expression on dendritic morphology. Murine neurons with reduced MOV10 and FMRP phenocopied Dicer1 KO neurons which exhibit impaired dendritic maturation Hong J (2013), leading us to hypothesize that MOV10 and FMRP regulate DICER expression. In cells and tissues expressing reduced MOV10 or no FMRP, DICER expression was significantly reduced. Moreover, the Dicer1 mRNA is a Cross-Linking Immunoprecipitation (CLIP) target of FMRP Darnell JC (2011), MOV10 Skariah G (2017) and AGO2 Kenny PJ (2020). MOV10 and FMRP modulate expression of DICER1 mRNA through its 3’untranslated region (UTR) and introduction of a DICER1 transgene restores normal neurite outgrowth in the Mov10 KO neuroblastoma Neuro2A cell line and branching in MOV10 heterozygote neurons. Moreover, we observe a global reduction in AGO2-associated microRNAs isolated from Fmr1 KO brain. We conclude that the MOV10-FMRP-AGO2 complex regulates DICER expression, revealing a novel mechanism for regulation of miRNA production required for normal neuronal morphology.

2019 ◽  
Author(s):  
Phillip J Kenny ◽  
Miri Kim ◽  
Geena Skariah ◽  
Joshua Nielsen ◽  
Monica C Lannom ◽  
...  

Abstract The Fragile X Mental Retardation Protein (FMRP) is an RNA binding protein that regulates translation and is required for normal cognition. FMRP upregulates and downregulates the activity of microRNA (miRNA)-mediated silencing in the 3′ UTR of a subset of mRNAs through its interaction with RNA helicase Moloney leukemia virus 10 (MOV10). This bi-functional role is modulated through RNA secondary structures known as G-Quadruplexes. We elucidated the mechanism of FMRP’s role in suppressing Argonaute (AGO) family members’ association with mRNAs by mapping the interacting domains of FMRP, MOV10 and AGO and then showed that the RGG box of FMRP protects a subset of co-bound mRNAs from AGO association. The N-terminus of MOV10 is required for this protection: its over-expression leads to increased levels of the endogenous proteins encoded by this co-bound subset of mRNAs. The N-terminus of MOV10 also leads to increased RGG box-dependent binding to the SC1 RNA G-Quadruplex and is required for outgrowth of neurites. Lastly, we showed that FMRP has a global role in miRNA-mediated translational regulation by recruiting AGO2 to a large subset of RNAs in mouse brain.


Author(s):  
U.I. Heine ◽  
G.R.F. Krueger ◽  
E. Munoz ◽  
A. Karpinski

Infection of newborn mice with Moloney leukemia virus (M-MuLV) causes a T-cell differentiation block in the thymic cortex accompanied by proliferation and accumulation of prethymic lymphoblasts in the thymus and subsequent spreading of these cells to generate systemic lymphoma. Current evidence shows that thymic reticular epithelial cells (REC) provide a microenvironment necessary for the maturation of prethymic lymphoblasts to mature T-lymphocytes by secretion of various thymic factors. A change in that environment due to infection of REC by virus could be decisive for the failure of lymphoblasts to mature and thus contribute to lymphoma development.We have studied the morphology and distribution of the major thymic cell populations at different stages of tumorigenesis in Balb/c mice infected when newborn with 0.2ml M-MuLV suspension, 6.8 log FFU/ml. Thymic tissue taken at 1-2 weekly intervals up to tumor development was processed for light and electron microscopy, using glutaraldehyde-OsO4fixation and Epon-Araldite embedding.


Author(s):  
N. Savage ◽  
A. Hackett

A cell line, UC1-B, which was derived from Balb/3T3 cells, maintains the same morphological characteristics of the non-transformed parental culture, and shows no evidence of spontaneous virus production. Survey by electron microscopy shows that the cell line consists of spindle-shaped cells with no unusual features and no endogenous virus particles.UC1-B cells respond to Moloney leukemia virus (MLV) infection by a change in morphology and growth pattern which is typical of cells transformed by sarcoma virus. Electron microscopy shows that the cells are now variable in shape (rounded, rhomboid, and spindle), and each cell type has some microvilli. Virtually all (90%) of the cells show virus particles developing at the cell surface and within the cytoplasm. Maturing viruses, typical of the oncogenic viruses, are found along with atypical tubular forms in the same cell.


1992 ◽  
Vol 12 (11) ◽  
pp. 4994-5003
Author(s):  
S J Tapscott ◽  
A B Lassar ◽  
H Weintraub

The MyoD gene can orchestrate the expression of the skeletal muscle differentiation program. We have identified the regions of the gene necessary to reproduce transcription specific to skeletal myoblasts and myotubes. A proximal regulatory region (PRR) contains a conserved TATA box, a CCAAT box, and a GC-rich region that includes a consensus SP1 binding site. The PRR is sufficient for high levels of skeletal muscle-specific activity in avian muscle cells. In murine cells the PRR alone has only low levels of activity and requires an additional distal regulatory region to achieve high levels of muscle-specific activity. The distal regulatory region differs from a conventional enhancer in that chromosomal integration appears necessary for productive interactions with the PRR. While the Moloney leukemia virus long terminal repeat can enhance transcription from the MyoD PRR in both transient and stable assays, the simian virus 40 enhancer cannot, suggesting that specific enhancer-promoter interactions are necessary for PRR function.


Neuron ◽  
2002 ◽  
Vol 34 (6) ◽  
pp. 961-972 ◽  
Author(s):  
Joannella Morales ◽  
P.Robin Hiesinger ◽  
Andrew J. Schroeder ◽  
Kazuhiko Kume ◽  
Patrik Verstreken ◽  
...  

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