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Welcome to The Visible Embryo, a comprehensive educational resource on human development from conception to birth.

The Visible Embryo provides visual references for changes in fetal development throughout pregnancy and can be navigated via fetal development or maternal changes.

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
CLICK ON weeks 0 - 40 and follow along every 2 weeks of fetal development
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Home | Pregnancy Timeline | News Alerts |News Archive Aug 22, 2014

 

 






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Embryonic cell fate sealed by the speed of a signal

When embryonic cells receive a signal to specialize, that signal can move quickly — or slowly. New research suggests the speed at which an embryonic cell receives a signal influences it’s fate.

Until now, the amount of chemical signals was thought to determinine if an embryonic cell would become muscle, skin, brain, bone or any other part of the body. This new research challenges that theory.


“It turns out that if ramped up slowly enough an otherwise potent signal generates no response in the receiving cells. Meanwhile, a pulsing, on-off signal appears to have a stronger effect than a constant, powerful one,”

Ali Brivanlou, PhD, Robert and Harriet Heilbrunn professor, and head of the Laboratory of Molecular Vertebrate Embryology at Rockefeller University.


To visualize a cells’ response to signals that ultimately lead to it's fate, researchers engineered a protein — Smad4 — to glow. In response to a pulse from signal molecules, Smad4 moves into the dark nuclei of the cell, causing it to glow briefly.


“Until now, it has not been feasible to test how speed affects a cell’s response to a signal.  However, by adapting time-lapse microscopy thereby creating very precise control, we found unequivocal evidence that signal level alone does not determine a cell’s fate. The consistency of the signal's presentation is also extremely important.”

Eric D. Siggia, PhD, Viola Ward Brinning and Elbert Calhoun Brinning Professor, Laboratory of Theoretical Condensed Matter Physics, at The Rockefeller.


Together, the team dubbed their discovery “speed fating.” Their work is published in Developmental Cell.

Biologists have known for about 50 years — that a cell determines its location and future role in the body based on chemical cues from neighboring cells. Developmental biologist Lewis Wolpert proposed that cell fate hinges on the intensity of the signal to which a cell is exposed. Above a certain intensity threshold, a cell has one fate, below that threshold, a different fate. Wolpert's theory is known as the French flag model — after a tri-color graph used to represent three cell fates with respect to the time at which each cell received a signal thereby creating three differnt fates.

Prior work from Brivanlou and Siggia had cast doubt on the importance of signal concentration. Using a common developmental signaling pathway known as TGF-β, they documented an adaptive response in cells exposed to TGF-β signaling molecules. This response peaked then declined over time, even though the signaling molecules remained constant.

To follow up on this work, Benoit Sorre, former Rockefeller postdoc now at the University of Paris, Diderot teamed up with Aryeh Warmflash, a postdoc who lead the previous TGF-β work. Together, they worked with mouse cells that have the potential to differentiate into muscle, or cartilage and bone. Progenitor cells like these can differentiate into a limited set of tissues, and are the offspring of stem cells. Their experiments exposed these progenitor cells to signaling molecules from the TGF-β pathway, and recorded the cells’ responses.


Sorre and Warmflash started with a continuous signal. As previous work suggested, this finger-stuck-on-the-buzzer approach did not produce a continuous response from the cells.

A second set of tests showed a series of brief pulses of signal produced a greater response than one continuous signal.


Gradually increasing the concentration of the signal, however, appeared to have the opposite effect. When researchers increased signal concentration — brief periods equalling five hours, long periods as much as 40 hours — the longer the period with a slower rate of increase generated the weakest cell response. The cells subjected to a 40-hour run barely registered at all.

Based on these experiments, the team created a mathematical model to describe how a cell in an embryo may relate its position to the source of a signal. It is still true that the fates of three cells can be mapped out based on their position, but the cells appear to arrive at these fates more rapidly than previously thought — thanks to the adaptive response that takes into account both the intensity and speed of a signal.

“This finding is another instance of a productive collaboration between biologists and physicists. Neither group, biologists or physicists, could have realized this result working alone,” Siggia says.

Highlights
•C2C12 cell response to a TGF-β concentration step is transient and adaptive
•Pulsed stimulation increases pathway throughput
•Cell response depends on the rate of ligand change as well as its final value
•Distance from a morphogen source can be learned from concentration increase rate

Summary
Genetics and biochemistry have defined the components and wiring of the signaling pathways that pattern the embryo. Among them, the transforming growth factor β (TGF-β) pathway has the potential to behave as a morphogen: in vitro experiments established that it can dictate cell fate in a concentration-dependent manner. How morphogens convey positional information in a developing embryo, when signal levels change with time, is less understood. Using integrated microfluidic cell culture and time-lapse microscopy, we demonstrate here that the speed of ligand presentation has a key and previously unexpected influence on TGF-β signaling outcomes. The response to a TGF-β concentration step is transient and adaptive: slowly increasing the ligand concentration diminishes the response, and well-spaced pulses of ligand combine additively, resulting in greater pathway output than with constant stimulation. Our results suggest that in an embryonic context, the speed of change of ligand concentration is an instructive signal for patterning.


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