Amazing work from @chivukula_raghu on how a repeat expansion causes disease by impairing tRNA splicing👇. This is very important work that illuminates how polyGlycine repeats cause neurodegeneration, similar to mutations in tRNA splicing factors. Congrats Raghu and team!.

Altogether, this study provides a valuable dataset that will facilitate identification of additional mammalian TDMD triggers and establishes the existence of a Plagl1/Lrrc58-mediated TDMD pathway that plays a major role in regulating mammalian body size. /End.

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Interestingly, Plagl1 encodes a transcription factor that promotes embryonic growth by transactivating Igf2 expression. This function likely synergizes with the noncoding function of this mRNA in removing the growth suppressing miRNA miR-322 through TDMD.

We further demonstrate that deletion of the trigger sites in the 3' UTRs of these mRNAs in mice results in miR-322/503-dependent embryonic growth restriction, thereby recapitulating a key aspect of the ZSWIM8-deficiency phenotype.

But the presumptive triggers that induce TDMD of miR-322/503 have remained elusive until now. We show here that Plagl1 and Lrrc58 are the long-sought trigger RNAs for TDMD of miR-322 and miR-503, respectively.

miR-322/503 were among the first miRNAs found to have short half-lives (Rissland et al., Mol Cell 2011). Moreover, we showed that a major phenotype in Zswim8 KO mice, embryonic growth restriction, is attributable to upregulation of miR-322/503 (Jones et al., Genes Dev, 2023).

Here, we applied a method called AGO-CLASH, which enables the detection of bona fide miRNA binding sites across the transcriptome. This revealed the triggers for TDMD of miR-322 and miR-503 in mice. These miRNAs are of particular interest for several reasons.

Although it is presumed that each of these miRNAs has an associated trigger RNA that activates ZSWIM8-mediated degradation, the identification of TDMD triggers has proven to be a very challenging problem, with only four mammalian trigger RNAs reported to date.

ZSWIM8 and its orthologs are required for normal development in flies, worms, and mice and, accordingly, many miRNAs are controlled by this mechanism across these species. For example, more than 50 ZSWIM8-regulated miRNAs have been identified in mouse tissues.

Our lab and the Bartel lab showed that this leads to recruitment of the ZSWIM8 ubiquitin ligase, which ubiquitylates the trigger-bound Argonaute (AGO) protein, resulting in decay of AGO by the proteasome and release and degradation of the associated miRNA.

In recent years, TDMD has emerged as a major mechanism that is critical for controlling microRNA (miRNA) expression during development in diverse metazoans. TDMD is activated when a miRNA binds to a specialized target RNA, referred to as a ‘trigger RNA’.

I am pleased to present our latest pre-print describing our identification of the long-sought triggers for target-directed microRNA degradation (TDMD) of miR-322 and miR-503, led by @ColletteLavigne and @Jaeil__Han. Read on for more info!👇

RT @WelchFoundation: Principal Investigator Joshua Mendell (@Mendell_lab) and researchers at @UTSWMedCenter highlight the functional versat….

Beautiful work with translational potential. Congrats Igor and team! (and thanks for providing something positive on this platform!).

It's difficult to focus on science with everything going on, but I still enjoy hearing about other people's work here, so I want to continue sharing ours. I am happy to re-post this thread about our pre-print that is now published in @MolecularCell.

Very exciting story from @ScientistJoanna @RuggeroDavide and colleagues! Great example of the importance of translational control in cancer and a very cool mechanism.

Hello Twitter friends! For those of you making the leap to the other place 🦋 please find me at:.Looking forward to seeing you there!.

RT @HHMINEWS: HHMI Investigator Joshua Mendell (@Mendell_lab) at @UTSWMedCenter helped discover that tRNAs play a role in stabilizing or de….

I’m thrilled to share this story from @Mendell_lab and Jan Erzberger labs, led by postdoc extraordinaire Xiaoqiang Zhu! We showed that in addition to their canonical decoding function, tRNAs play a key role in regulating mRNA stability during translation.

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