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Today, The Visible Embryo is linked to over 600 educational institutions and is viewed by more than 1 million visitors each month. The field of early embryology has grown to include the identification of the stem cell as not only critical to organogenesis in the embryo, but equally critical to organ function and repair in the adult human. The identification and understanding of genetic malfunction, inflammatory responses, and the progression in chronic disease, begins with a grounding in primary cellular and systemic functions manifested in the study of the early embryo.

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Pregnancy Timeline by SemestersFetal liver is producing blood cellsHead may position into pelvisBrain convolutions beginFull TermWhite fat begins to be madeWhite fat begins to be madeHead may position into pelvisImmune system beginningImmune system beginningPeriod of rapid brain growthBrain convolutions beginLungs begin to produce surfactantSensory brain waves begin to activateSensory brain waves begin to activateInner Ear Bones HardenBone marrow starts making blood cellsBone marrow starts making blood cellsBrown fat surrounds lymphatic systemFetal sexual organs visibleFinger and toe prints appearFinger and toe prints appearHeartbeat can be detectedHeartbeat can be detectedBasic Brain Structure in PlaceThe Appearance of SomitesFirst Detectable Brain WavesA Four Chambered HeartBeginning Cerebral HemispheresFemale Reproductive SystemEnd of Embryonic PeriodEnd of Embryonic PeriodFirst Thin Layer of Skin AppearsThird TrimesterSecond TrimesterFirst TrimesterFertilizationDevelopmental Timeline
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Home | Pregnancy Timeline | News Alerts |News Archive Aug 19, 2014

Dis3l2 is a protein that preserves the flexibility of stem cells by degrading messages inside its funnel
shape as more than a dozen contacts capture the poly-U mark, destroying an entire message.
Credit: Leemor Joshua-Tor, Cold Spring Harbor Laboratory

 






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How enzymes know what to keep or trash in a cell

The protein Dis3l2 uses numerous recognition sites to capture messages that are flagged for decay.

Every once in a while, we are forced to sort that stack of papers on the kitchen counter. Between expired coupons and dozens of takeout menus are important documents like car insurance or an electric bill. So it isn't an option to simply drop it all in the trash at once – you need to read through the messages to be sure that vital data isn't lost.

In the cell, proteins read through a cell's "message" stack to distinguish what messages need to be saved and which need to be discarded just as we do. But in the cell, messages that are marked for disposal can drastically alter a cell's fate. Reading messages and discarding unnecessary ones, is the same system used by stem cells to maintain their flexible identity.

In the stem cell, the protein Dis3l2 acts as a shredder of messages. It prevents stem cells from changing into other cell types by cutting up messages that encode for other cell types. But Dis3l2 is highly specific. It only targets messages that have been marked with a molecular flag, known as a "poly-U" chain. It ignores the majority of messages in the cell whose ends are decorated with a different type of chain, called a "poly-A" tail.

Cold Spring Harbor Laboratory (CSHL) scientists, led by Professor and Howard Hughes Medical Institute Investigator Leemor Joshua-Tor, describe how Dis3l2 uses numerous recognition sites to capture messages that are flagged for decay. Using X-ray crystallography, they also saw how Dis3l2 is able to distinguish between the two chains. Their work is published in the journal Nature.


"We saw that the enzyme looks a lot like funnel, quite wide at the top and narrow at the base. The poly-U chain inserts itself into the depths of this funnel while the rest of the bulky message remains in the wide mouth at the top."

Leemor Joshua-Tor, PhD, lead author, CSHL.

"Together, all of the poly-U chain points create a sticky web that holds the poly-U sequence deep within the enzyme. But other chains don't interact – they slide right out. This discovery has helped us understand how an enzyme can differentiate between two sequences in the cell."

Christopher Faehnle, PhD, second lead author, CSHL.


Faehnle and Jack Walleshauser found the interior of the funnel contains more than a dozen contacts that interact specifically with the poly-U chain.

"Misregulation of any step in this pathway leads to developmental disorders and cancer,"
says Joshua-Tor. "But, we now have a much better appreciation of the terminal step - a critical point of control."

Abstract
The pluripotency factor Lin28 inhibits the biogenesis of the let-7 family of mammalian microRNAs1, 2, 3, 4. Lin28 is highly expressed in embryonic stem cells and has a fundamental role in regulation of development5, glucose metabolism6 and tissue regeneration7. Overexpression of Lin28 is correlated with the onset of numerous cancers8, whereas let-7, a tumour suppressor, silences several human oncogenes5. Lin28 binds to precursor let-7 (pre-let-7) hairpins9, triggering the 3′ oligo-uridylation activity of TUT4 and TUT7 (refs 10, 11, 12). The oligoU tail added to pre-let-7 serves as a decay signal, as it is rapidly degraded by Dis3l2 (refs 13, 14), a homologue of the catalytic subunit of the RNA exosome. The molecular basis of Lin28-mediated recruitment of TUT4 and TUT7 to pre-let-7 and its subsequent degradation by Dis3l2 is largely unknown. To examine the mechanism of Dis3l2 substrate recognition we determined the structure of mouse Dis3l2 in complex with an oligoU RNA to mimic the uridylated tail of pre-let-7. Three RNA-binding domains form an open funnel on one face of the catalytic domain that allows RNA to navigate a path to the active site different from that of its exosome counterpart. The resulting path reveals an extensive network of uracil-specific interactions spanning the first 12 nucleotides of an oligoU-tailed RNA. We identify three U-specificity zones that explain how Dis3l2 recognizes, binds and processes uridylated pre-let-7 in the final step of the Lin28–let-7 pathway.


This work was supported by Watson School of Biological Sciences, the Louis Morin Charitable Trust and the Robertson Research Fund of Cold Spring Harbor Laboratory.

"Mechanism of Dis3l2 substrate recognition in the Lin28–let-7 pathway" appears online in Nature on August 3, 2014. The authors are: Christopher Faehnle, Jack Walleshauser and Leemor Joshua-Tor. The paper can be obtained online at: http://dx.doi.org/10.1038/nature13553

About Cold Spring Harbor Laboratory
Founded in 1890, Cold Spring Harbor Laboratory (CSHL) has shaped contemporary biomedical research and education with programs in cancer, neuroscience, plant biology and quantitative biology. CSHL is ranked number one in the world by Thomson Reuters for the impact of its research in molecular biology and genetics. The Laboratory has been home to eight Nobel Prize winners. Today, CSHL's multidisciplinary scientific community is more than 600 researchers and technicians strong and its Meetings & Courses program hosts more than 12,000 scientists from around the world each year to its Long Island campus and its China center. For more information, visit http://www.cshl.edu.


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