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The National Institutes of Child Health and Human Development awarded Phase I and Phase II Small Business Innovative Research Grants to develop The Visible Embryo. Initally designed to evaluate the internet as a teaching tool for first year medical students, The Visible Embryo is linked to over 600 educational institutions and is viewed by more than one million visitors each month.

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 June 24, 2014

Restoring one interaction — between Grb2 and a protein known as Ptpn11/Shp2
phosphatase — was enough to allow stem cells to change into other cell types.

 






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Key protein in embryo stem cell differentiation found

Proteins are responsible for the majority of cell functions, but as they interact within complex networks, determining which are more significant than others is difficult. However, new research may have identified a simpler way to find the proteins critical to a network's function — even to the first moment of differentiation.

New research from the University of Chicago has pioneered a technique to simplify the study of protein networks and identify the importance of specific protein interactions. By designing synthetic proteins that only interact with pre-determined partners, scientists have revealed the key interaction regulating when embryonic stem cells begin to differentiate.

They describe their findings June 5 in Molecular Cell.


"Our work suggests that the apparent complexity of protein networks is deceiving, and that a circuit involving a small number of proteins might control each cellular function,"

Shohei Koide, PhD, senior author, professor, biochemistry and molecular biophysics, University of Chicago


Diagrammed protein networks can resemble a subway map out of hell. Such networks traditionally have been studied by removing a protein of interest through genetic engineering, then observing whether that removal destroys the intended function of the network, or not. However, this methodology doesn't identify individual protein-to-protein interactions.

Koide's team has pioneered a new technique they call "directed network wiring." They removed a protein essential for a cell's transformation into other cell types — Grb2 — then engineered synthetic versions of Grb2 to interact with only one protein from a pool of dozens it normally networks with. Re-introducing each of these synthetic proteins back into the cell, they were able to record each specific interaction that restored a stem cell's transformative abilities.

Koide: "The name, 'directed network wiring,' comes from the fact that we create minimalist networks. We first remove all communication lines associated with a protein of interest and add back a single line. It is analysis by addition."


Despite the complexity of the protein network associated with stem cell development, the team discovered that restoring only one interaction — between Grb2 and a protein known as Ptpn11/Shp2 phosphatase — was enough to allow stem cells to again change into other cell types.


"We were really surprised to find that consolidating many interactions into a single connection for the protein was sufficient to support development of the next stage involving many complicated processes," Koide said. "Our results show that signals travel discrete and simple routes in the cell."

Koide and his team are now working on streamlining directed network wiring and applying it to other areas of study such as cancer. With the ability to dramatically simplify protein interaction networks, they hope to open the door to new research areas and therapeutic approaches.

He adds: "We can now design synthetic proteins far more sophisticated than natural ones, and use such super-performance proteins toward advancing science and medicine."

Highlights
•Defining roles of individual interactions in complex networks is challenging
•Protein design tailors Grb2 SH2 into “pY-clamps” specific for single pY-ligands
•Rewiring the Grb2 PPI network using synthetic Grb2 comprising pY-clamps
•Identified Ptpn11 pY580 as a key Grb2 SH2 ligand in stem cell fate specification

Summary
Cell signaling depends on dynamic protein-protein interaction (PPI) networks, often assembled through modular domains each interacting with multiple peptide motifs. This complexity raises a conceptual challenge, namely to define whether a particular cellular response requires assembly of the complete PPI network of interest or can be driven by a specific interaction. To address this issue, we designed variants of the Grb2 SH2 domain (“pY-clamps”) whose specificity is highly biased toward a single phosphotyrosine (pY) motif among many potential pYXNX Grb2-binding sites. Surprisingly, directing Grb2 predominantly to a single pY site of the Ptpn11/Shp2 phosphatase, but not other sites tested, was sufficient for differentiation of the essential primitive endoderm lineage from embryonic stem cells. Our data suggest that discrete connections within complex PPI networks can underpin regulation of particular biological events. We propose that this directed wiring approach will be of general utility in functionally annotating specific PPIs.

The study, "Directed network wiring identifies a key protein interaction in embryonic stem cell differentiation," was supported by the National Institutes of Health. Additional authors include Norihisa Yasui, Greg M. Findlay, Gerald D. Gish, Marilyn S. Hsiung, Jin Huang, Monika Tucholska, Lorne Taylor, Louis Smith, W. Clifford Boldridge, Akiko Koide and Tony Pawson.

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