Nav: Home

Embryos' signals take multiple paths

March 07, 2019

Rice University scientists have found significant differences between the methods signaling pathways use to prompt cells to differentiate - that is, whether to become organs, bone, blood vessels, nerves or skin.

Rice bioscientist Aryeh Warmflash and alumnus Idse Heemskerk led a team that discovered stem cells are sensitive not only to the signals that form the "instructions" to create the pattern of the organism, but to how rapidly those signals are delivered.

The lab set out to see if the amount of the signaling molecule was the primary cue for instructing the cells what to become.

The answer was clearly "no" for one of the highly related pathways they studied - and, surprisingly, "yes" for the other.

The open-access paper in eLife details the activities of two signaling pathways, Nodal and BMP4, in experimental models of early mammalian embryos.

Both pathways are integral to the process known as gastrulation, when the body plan of the embryo is created. BMP4 triggers the process and defines the "ventral" or belly side of the embryo, where skin will form. On the opposite side, where BMP is low, the nervous system develops. When cells are exposed to BMP, it sustains change for as long as its triggering ligand is present.

In contrast, the Nodal pathway, which causes cells to become muscle, the heart and other organs, is controlled by how its target cells sense and adapt to changes in the environment, especially to changing levels of its ligand.

The researchers concluded interactions between these ligands, called morphogens, and cells are far more dynamic than previously thought, and not merely dependent on ligand concentration.

The Rice lab employs a unique experimental system mimicking growth in confined spaces that allows human embryonic stem cells to divide and differentiate, but in a controlled shape similar to that of the embryo. It lets researchers perturb a colony with proteins that trigger specific pathways to see how they interact with differentiating cells and with each other.

Recently, the lab determined the WNT signaling pathway that carries signals across a cell membrane depends upon context for its actions. Nodal and BMP4 are part of the TGFb superfamily of proteins. The researchers found they alter how cells respond to WNT.

"What's true for WNT is even more so for the TGFb pathways we looked at this time," said Warmflash, an assistant professor of biosciences. "For WNT, we highlighted how the same pathway can be deployed in different ways depending on context. This paper highlights how different pathways that function in parallel, almost in the same context, get used differently."

Nodal and BMP4 are triggered by their matching ligands during gastrulation. In the 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). That allowed them to monitor the pathways' activities.

"These pluripotent cells decide between 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 said. "Over three days, cells make these decisions at the same time they're undergoing morphogenesis, which puts all those layers in the right place."

Researchers once thought high signal in one area of the embryo and low signal in another determined differentiation, but the Rice lab's experiments showed otherwise. "We don't think cells are sensing high versus low," Warmflash said. "They're sensing whether the pathways, triggered by the presence of ligands, are turning on fast versus turning on slow."

The Nodal pathway was most interesting. "Essentially, it's always transient," Warmflash said. "In the naïve picture, you might think of this pathway as a switch. But why does the signal turn off when the switch is on? Well, that's what it does.

"It's important because it means the cells sense when the levels in the 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 the dynamics."

In experiments, the cells produced their own Nodal ligand as part of recreating the early embryo-like patterns. The researchers saw a wave of Nodal signaling sweep through the colonies at a rate of about one cell width per hour, Warmflash said. "Right after a wave comes through is when we see the differentiation markers that determine cell fates," he said.

The researchers gained a measure of control over differentiation by pulsing the colony's exposure to the ligand for one hour and removing it for six hours over three cycles.

"We showed those three hours of exposure, timed properly, drives differentiation of the cells better than 20 hours of exposure," Warmflash said. "We think that by understanding the dynamics, we will have a way to drive cells to particular fates and also to understand how those pathways work as cells make patterns during development."
Former technician Kari Burt, undergraduate Matthew Miller, graduate student Sapna Chhabra and research technician M. Cecilia Guerra, all of Rice, are co-authors of the paper. Heemskerk is now an assistant professor of cell and developmental biology at the University of Michigan Medical School.

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.

Read the paper at

This news release can be found online at

Follow Rice News and Media Relations via Twitter @RiceUNews.

Related materials:

Embryos' signaling proteins go with the flow:

Warmflash Lab:

Heemskerk Lab:

Rice Department of BioSciences:

Wiess School of Natural Sciences:


A video shows the Nodal wave moving inwards as cells differentiate en route to their ultimate fates in an organism. The image shows the activated SMAD4 proteins in the nuclei of cells, tagged with green fluorescent proteins that allowed Rice University bioscientists to monitor them. The right image shows the same cells, color-coded by the strength of their signals. (Credit: Warmflash Lab/Rice University)

Located on a 300-acre forested campus in Houston, Rice University is consistently ranked among the nation's top 20 universities by U.S. News & World Report. Rice has highly respected schools of Architecture, Business, Continuing Studies, Engineering, Humanities, Music, Natural Sciences and Social Sciences and is home to the Baker Institute for Public Policy. With 3,962 undergraduates and 3,027 graduate students, Rice's undergraduate student-to-faculty ratio is just under 6-to-1. Its residential college system builds close-knit communities and lifelong friendships, just one reason why Rice is ranked No. 1 for lots of race/class interaction and No. 2 for quality of life by the Princeton Review. Rice is also rated as a best value among private universities by Kiplinger's Personal Finance.

Rice University

Related Nervous System Articles:

Rare cells are 'window into the gut' for the nervous system
Specialized cells in the gut sense potentially noxious chemicals and trigger electrical impulses in nearby nerve fibers, according to a new study led by UC San Francisco scientists.
Study overturns seminal research about the developing nervous system
New research by scientists at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA overturns a long-standing paradigm about how axons grow during embryonic development.
Sympathetic nervous system is critical in regulating energy expenditure and thermogenesis
New study suggests that your brain, not your white blood cells, keeps you warm.
As fins evolve to help fish swim, so does the nervous system
The sensory system in fish fins evolves in parallel to fin shape and mechanics, and is specifically tuned to work with the fish's swimming behavior, according to new research from the University of Chicago.
Antibodies as 'messengers' in the nervous system
Antibodies are able to activate human nerve cells within milliseconds and hence modify their function -- that is the surprising conclusion of a study carried out at Human Biology at the Technical University of Munich (TUM).
Bioimaging: A clear view of the nervous system
A new and versatile imaging technique enables researchers to trace the trajectories of whole nerve cells and provides extensive insights into the structure of neuronal networks.
In the gut, nervous cells are the 'eyes and ears' of the immune system
A team of scientists in Portugal has discovered, in the mouse gut, a novel process that protects the bowel's lining against inflammation and microbial aggressions -- and fights them when they arise.
Biologists discover new strategy to treat central nervous system injury
Neurobiologists at UC San Diego have discovered how signals that orchestrate the construction of the nervous system also influence recovery after traumatic injury.
Delivery strategies of chemotherapy to the central nervous system
The blood-brain barrier and the blood-tumor barrier remain great obstacles to the drug delivery to brain tumors.
520-million-year-old fossilized nervous system is most detailed example yet found
A 520-million-year-old fossilized nervous system -- so well-preserved that individually fossilized nerves are visible -- is the most complete and best example yet found, and could help unravel how the nervous system evolved in early animals.

Related Nervous System Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Moving Forward
When the life you've built slips out of your grasp, you're often told it's best to move on. But is that true? Instead of forgetting the past, TED speakers describe how we can move forward with it. Guests include writers Nora McInerny and Suleika Jaouad, and human rights advocate Lindy Lou Isonhood.
Now Playing: Science for the People

#527 Honey I CRISPR'd the Kids
This week we're coming to you from Awesome Con in Washington, D.C. There, host Bethany Brookshire led a panel of three amazing guests to talk about the promise and perils of CRISPR, and what happens now that CRISPR babies have (maybe?) been born. Featuring science writer Tina Saey, molecular biologist Anne Simon, and bioethicist Alan Regenberg. A Nobel Prize winner argues banning CRISPR babies won’t work Geneticists push for a 5-year global ban on gene-edited babies A CRISPR spin-off causes unintended typos in DNA News of the first gene-edited babies ignited a firestorm The researcher who created CRISPR twins defends...