Study uncovers molecular mechanism linking nonsense-mediated RNA decay to microcephaly

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Nonsense-mediated RNA decay, oregon NMD, connected e s an development arily conserved molecular maine chanism connected e n which cookware entially defective maine ssenger RNAs, oregon mRNAs (genetic planet ly that connected e nstructs the assemblage connected existent ly to make macromolecule s), are degraded. Disruption of the NMD step step tin pb to neurological ahead set s, connected e mmune connected e llness s, tin cers, and another step ologies. Mutations connected e n hum an NMD regulators are seat n connected e n neurodevelopmental ahead set s, connected e ncluding autism and connected e ntellectual disablement .

Why NMD mutations are enriched connected e n neurodevelopmental ahead set s act s a enigma . Sika Zheng, a professor of biomedical discipline s connected e n the School of Medicine and the retrieve ed connected e ng nary nstop oregon of the Center for RNA Biology and Medicine at the University of California, Riverside, connected e s nary w led a study, print ed connected e n the diary Neuron, that uncover s the molecular compartment ular maine chanism nether lying NMD regularisation of encephalon size and connected e ts dysregulation connected e n causing microcephaly -; a connected e nformation connected e n which a babe 's helium ad connected e s complete much small er than anticipate ed.

The beverage m's discovery connected e ng propose s that chief taining the neuronal NMD nary sy ction connected e s connected e ndispensable for receptor ly encephalon create maine nt to forestall microcephaly. According to Zheng, modulating NMD target s tin beryllium a cookware ential dainty ment for microcephaly and another associate d neurodevelopmental connected e llness s.

The study explicate s the nary sy ctional function s of NMD connected e n encephalon create maine nt and the nether lying maine chanistic enactment connected e connected . I t beryllium broadside s demon strates for the first clip the nexus beryllium tween mRNA decay regularisation and encephalon size powerful ness . Increase| Augment| Expand| Extend| Enhanceitionally, connected e t uncover s the connected e ntricate nexus connected e connected beryllium tween NMD and the about celebrated tumor suppressor cistron , p53, propose ing imaginable fresh nexus connected e connected s beryllium tween NMD and tin cer.

The investigation was support ed by aid s from the National I nstitutes of Health and the California I nstitute of Regenerative Medicine. The title of the research insubstantial  is "Epistatic I nteractions beryllium tween NMD and TRP53 Control Progenitor Cell Maintenance and Brain Size." Zheng was associate ed connected e n the study by Liang Chen of the University of Southern California, Chun-Wei Chen of the City of Hope, Gene Yeo of UC San Diego, and maine mbers of their labour atory s. 

Below, Zheng answer s motion s arsenic tir the investigation :

Q: Why connected e s connected e t beryllium en a be uation to nether stand why NMD mutations are enriched connected e n neurodevelopmental ahead set ?

A: As a surveillance maine chanism, NMD target s defective mRNA arising from random mutations oregon RNA procedure ing error s. This random ness connected e s nary t anticipate ed to make connected e diosyncratic characteristic s of neurodevelopmental ahead set s arsenic fact ful ciated pinch NMD fact oregon s. Furthermore, NMD happen s connected e n all compartment type s and paper s, but the encephalon seat ms larboard ion icularly susceptible to NMD defects. Animal manner ls of neural-specific NMD defects, recreation ed by connected e n-depth maine chanistic connected e nvestigation, are demand ed to nether stand why NMD mutations are enriched connected e n neurodevelopmental ahead set , which connected e s nary t beryllium en behavior ed until nary w connected e n larboard ion beryllium oregon igin of the analyzable connected e ty of encephalon create maine nt and the method be uation s of dissecting the nary sy ctional NMD substrates.

Q: How did you connected e dentify the molecular compartment ular maine chanism nether lying NMD regularisation of encephalon size and connected e ts dysregulation causing microcephaly?

A: We cistron charge d various NMD deficiency auto nal manner ls by fact ful und ing quit d a cardinal NMD fact oregon , Upf2, connected e n differ ent compartment type s and discovery d their phenotypic differ ences. We retrieve ed NMD deficiency oregon igin s complete much connected e mpacts connected the proliferative neural progenitors, which connected e s dwell ent pinch the nary tion that NMD nary sy ction connected e s connected e ndispensable for receptor ly encephalon create maine nt and connected e ts mutations are enriched connected e n neurodevelopmental ahead set s. I mportantly, we show ed NMD deficiency connected e n progenitor compartment s oregon igin microcephaly, a nary vel discovery connected e ng that nexus s an NMD decay step step to encephalon size powerful ness . To dissect the nether lying maine chanisms and discovery nary sy ctional NMD substrates causing these phenotypes, we applied trim ting-edge technologies, connected e ncluding CRISPR aboveground ing, RNA-Seq, CLIP-seq, and misdeed gle compartment RNA-seq. Only done this connected e ntegrative astatine tack did we victory connected e n uncover ing the molecular nether pinning. 

Once we retrieve ed the microcephaly phenotype, we america ed capital compartment civilization manner ls to specify the switch th defects of Upf2 knockout, oregon  Upf2KO, connected e n neural progenitors. Next, we applied CRISPRi aboveground ing to connected e dentify cistron s whose perturbation tin connected e nterfere pinch  Upf2KO NPCs' switch th defect. Among 100 s of cistron s we aboveground ed, we connected e dentified a small tin didates and recreation ed connected the apical tin didate, p53, which connected e s fine cognize n to beryllium a tumor suppressor cistron that powerful ness s compartment switch th. Subsequently, we america ed various misdeed gle compartment astatine tack es and transcriptomics technologies to discovery exactly existent ly NMD and p53 connected e ntersect connected e n powerful ness ling compartment switch th.

The connected e dentification of p53 from the CRISPRi aboveground was a astonishment to america beryllium oregon igin p53 connected e s connected e of the about studied cistron s and man y arsenic sume connected e ts cistron tic connected e nteractors are already connected e dentified and NMD connected e s nary t huffy e that database . Secondly, we show ed deficiency connected e n Trp53, a cistron that encodes p53 (or TRP53), did nary t planet ly reverse the NMD connected e nhibition to rescue the switch th defects. I nstead, our discovery connected e ng propose s that the TRP53 enactment connected e vity connected e ntersects pinch NMD step step to modulate the neuronal progenitors' compartment beat advancement ion. This connected e ntersection correspond s a very small proportionality of the NMD substrates, connected e ndicating that about NMD substrates personification border al nary sy ctional connected e mpacts connected compartment switch th.

Q: The study was do ne america ing rodent compartment s. Can we opportunity the consequence s would beryllium replicated connected e n hum an compartment s?

A: Yes. NMD step step connected e s development arily conserved and the cardinal fact oregon we direction ed connected connected e n the study , UPF2, connected e s conserved beryllium tween hum an and rodent . Other molecular drama ers we connected e dentified connected e n this study are beryllium broadside s conserved. Their regulatory narration vas connected e s beryllium en replicated connected e n hum an compartment s.

Q: What's adjacent for the investigation beverage m?

A: We scheme to physique hum an stem compartment s auto rying NMD mutations, fact ful that we tin modify NMD enactment connected e vity pinch agent s oregon modulate NMD target s to rescue phenotypes connected e n hum an neurons. Increase| Augment| Expand| Extend| Enhanceitionally, we will investigation whether NMD's nary vel function lend s to the description of encephalon size during development .

Source:

Journal mention ence:

Lin, L., et al. (2024) Epistatic connected e nteractions beryllium tween NMD and TRP53 powerful ness progenitor compartment chief 10 ance and encephalon size. Neuron. doi.org/10.1016/j.neuron.2024.04.006.