'Left-handers' tighten control over embryonic development

According to Rice University bioscientists, this inhibitory protein is key in the early stages of life, when the fate of embryonic stem cells is determined by the nodal signaling pathway

Experiments led by Aryeh Warmflash's lab at Rice University and postdoctoral researcher Lizhong Liu have visualized for the first time the mechanisms by which Nodal and Lefty interact to determine the future body planning of mammalian embryos

Their findings were published in the open-access journal Nature Communications

The study not only shows how Nodal signaling molecules called morphogens are controlled by Lefty, but also shows that Nodal proteins are delivered directly from one cell to another, triggering receptors to transcribe new Nodals

"Basically, instead of a gradient of proteins forming and instructing cells to become different types of cells, what we're showing is that the molecules involved don't diffuse at all," Warmflash said

The unique experimental model developed by Warmflash and his team over the years allowed them to see the early stages of gastrulation, where differentiation occurs

But so far, visualizing Nodal has been a problem

"We needed to be sure that the fluorescent label wouldn't affect function," said Liu, who spent two years looking for a solution

Once the label was determined to be benign, the lab began tracking Nodal's progression in cell lines with different configurations, and with or without Lefty's two human variants, for up to 42 hours

The ability to track individual proteins in mammalian systems could lead to the discovery of the mechanisms by which morphogenesis and its inhibitors take over its territory, Liu said

Traditionally, patterns have been thought to be due to some proteins diffusing faster than others, and the activity of local Nodal could lead to the creation of Lefty, which diffuses farther than Nodal and confines the signal to a specific range, he says of the theory.

To the researchers' surprise, direct observations of the endogenous molecule showed no signs of Nodal diffusion

The lab was able to show that this is necessary for waves by creating cells that lack the Nodal protein

The researchers also found that while Lefty did not spread in gastrulation experiments, it could travel longer distances in other conditions

"We wanted to understand what determines the diffusion rate of Lefty proteins in a specific environment," Liu said

"The other thing we're interested in is understanding how Node and Lefty work with other cofactors to define the body axis," he said.

Lizhong Liu, Anastasiia Nemashkalo, Luisa Rezende, Ji Yoon Jung, Sapna Chhabra, M.
Cecilia Guerra, Idse Heemskerk, Aryeh Warmflash.
Nodal is a short-range morphogen with activity that spreads through a relay mechanism in human gastruloids .
Nature Communications , 2022 ; 13 (1)