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Pregnancy Timeline by SemestersDevelopmental TimelineFertilizationFirst TrimesterSecond TrimesterThird TrimesterFirst Thin Layer of Skin AppearsEnd of Embryonic PeriodEnd of Embryonic PeriodFemale Reproductive SystemBeginning Cerebral HemispheresA Four Chambered HeartFirst Detectable Brain WavesThe Appearance of SomitesBasic Brain Structure in PlaceHeartbeat can be detectedHeartbeat can be detectedFinger and toe prints appearFinger and toe prints appearFetal sexual organs visibleBrown fat surrounds lymphatic systemBone marrow starts making blood cellsBone marrow starts making blood cellsInner Ear Bones HardenSensory brain waves begin to activateSensory brain waves begin to activateFetal liver is producing blood cellsBrain convolutions beginBrain convolutions beginImmune system beginningWhite fat begins to be madeHead may position into pelvisWhite fat begins to be madePeriod of rapid brain growthFull TermHead may position into pelvisImmune system beginningLungs begin to produce surfactant
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Developmental Biology - Cell Signals

Embryos 'Go With The Flow'

'Signalling pathways' are far more dynamic than once thought...

Rice University scientists have found significant differences between two methods 'signaling pathways' use to prompt cells to differentiate into organs such as bone, blood vessels, nerves or skin. Bioscientist Aryeh Warmflash and Rice University alumnus Idse Heemskerk, led a team discovering that stem cells are sensitive not only to signals that give 'instructions' to create pattern in an organism, but also how rapidly those signals are delivered.
The scientists found the WNT pathway not only listens for signals from a wider range of triggers than previously known, thus influencing the identity of many new cell types those new cell types also begin changing how they interpret WNT signals.

The lab set out to find if the amount of signaling molecule was the primary cue for instructing cells what to become and the answer was clearly "No" for one highly related pathway and a surprising "Yes" for the other.

The paper published in the open-access journal eLife gives details of two signaling pathways, Nodal and BMP4, as used in models of early mammalian embryos. Both are integral to the process known as gastrulation, when the body plan of the embryo is created.
BMP4 triggers gastrulation which defines the "ventral" or belly side of the embryo, and where skin will begin to form.

On the opposite side or "top", BMP4 quantity is low, and cells develop into the nervous system. BMP exposure sustains change as long as a triggering ligand is present.

In contrast, the Nodal pathway causes cells to become muscle such as the heart. Nodal is controlled by how its target cells sense and adapt to changes in environment, specifically changes in levels of its ligands.

Researchers concluded that Interactions between these ligands, or morphogens, and cells are far more dynamic than previously thought, and not merely dependent on the amount of ligands present.

The Rice lab uses a unique experimental system mimicking growth in confined spaces allowing human embryonic stem cells to divide and differentiate in a shape similar to that of an embryo. This allows researchers to perturb a colony with proteins to trigger specific signal pathways and observe interactions on differentiating cells - and all other cells.
Recently the WNT signaling pathway, which carries signals across a cell membrane, was found to depend upon context for its actions (PNAS). Nodal and BMP4 are part of the TGFb superfamily of proteins. Researchers found Nodal and BMP4 alter how cells respond to WNT.

According to Aryeh Warmflash PhD, assistant professor of biosciences at Rice: "For WNT, we highlighted how the WNT pathway can be deployed in different ways depending on context. This current paper highlights how different pathways that function in parallel - almost in the same context - get used differently."
Nodal and BMP4 are triggered by matching ligands during gastrulation. In that process, both access a protein known as Smad4, which moves into the cell's nucleus when activated - and can be tagged with green fluorescent protein (GFP). This allows scientists to monitor any pathway Smad4 tags.

"These pluripotent cells decide between [becomming] different germ layers - the ectoderm, which goes on to become the nervous system and skin; the mesoderm, which forms bone, blood and muscle, and the endoderm, which forms the digestive tract and other organs," Warmflash explains. "Over three days, cells make these decisions at the same time they're undergoing morphogenesis, which puts all those layers in the right place."

Warmflash finds the Nodal pathway fascinating. "Essentially, it's always transient. In the nave picture, you might think of this pathway as a switch. But why does the [Nodal] signal turn off when the switch is on?
Researchers once thought high signal in one area of an embryo and low signal in another determined differentiation, but the Rice lab's experiments show otherwise.

"We don't think cells are sensing high versus low," says Warmflash. "They're sensing whether the pathways, triggered by the presence of ligands, are turning on fast versus turning on slow."

"This is important because it means cells sense when levels of a pathway change. They don't sense, 'It's here, I turn on.' They sense, 'OK, it's changing, so I turn on.' That gives them sensitivity to [flow] dynamics."

Aryeh Warmflash PhD, Assistant Professor, Department of Biosciences and Department of Bioengineering, Rice University, Houston, Texas, USA.

In experiments, cells produced their own Nodal ligand while recreating early embryo-like patterns. After researchers observed a wave of Nodal signaling sweep through colonies at a rate of one cell width per hour, they gained a measure of control over differentiation by pulsing Nodal through cell colonies for one hour, removing it for six hours and repeat over three cycles.
"Right after a wave comes through, we see differentiation markers that determine cell fates. We saw those three hours of exposure, timed properly, drive differentiation of cells better than 20 hours of exposure. We think by understanding these dynamics, we will have a way to drive cells into particular fates. "

Aryeh Warmflash PhD

During embryonic development, diffusible signaling molecules called morphogens are thought to determine cell fates in a concentration-dependent way. Yet, in mammalian embryos, concentrations change rapidly compared to the time for making cell fate decisions. Here, we use human embryonic stem cells (hESCs) to address how changing morphogen levels influence differentiation, focusing on how BMP4 and Nodal signaling govern the cell-fate decisions associated with gastrulation. We show that BMP4 response is concentration dependent, but that expression of many Nodal targets depends on rate of concentration change. Moreover, in a self-organized stem cell model for human gastrulation, expression of these genes follows rapid changes in endogenous Nodal signaling. Our study shows a striking contrast between the specific ways ligand dynamics are interpreted by two closely related signaling pathways, highlighting both the subtlety and importance of morphogen dynamics for understanding mammalian embryogenesis and designing optimized protocols for directed stem cell differentiation.

Idse Heemskerk, Kari Burt, Matthew Miller, Sapna Chhabra, M Cecilia Guerra, Lizhong Liu and Aryeh Warmflash.

The authors declare no conflict of interest.

The work was funded by grants from the Cancer Prevention and Research Institute of Texas, the National Science Foundation and the Gillson Longenbaugh Foundation. Heemskerk was supported by a Branco Weiss Society in Science fellowship.

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Mar 14, 2019   Fetal Timeline   Maternal Timeline   News  

Green fluorescence tags a colony of human endothelial stem cells, showing high activity
as they organize themselves into patterns, 40 hours after BMP4 signaling is activated.
Rice University bioscientists carry out experiments on contained colonies of embryo stem
cells learning new details on what triggers them to differentiate into unique cell subtypes.
Image Credit: Warmflash Lab/Rice University

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