From the moment an embryo starts to take shape, two-way communication is critical for making sure tissues and organs develop correctly.

Two of the first physical structures to form in the embryo are the neural tube and the somites, which later go on to become the central nervous system and the spine, ribs, and skeletal muscles, respectively. These structures have been studied in animals, but entangling the huge array of messages between embryonic structures in humans is complicated. 

“We can’t study the dynamic formation of these tissues using human embryos as they develop relatively late and, ethically, we can’t culture embryos for more than fourteen days,” says Naomi Moris, who leads the Developmental Models Laboratory at the Crick. “Instead, we turn to lab-grown embryo models, which aren’t as complex as real embryos, but do allow us to hone in on one feature at a time to unpick how these interactions occur.” 

The lab develops such models using human pluripotent stem cells, which can become any cell in the body. These stem cells are grown in defined conditions to create 3D structures that mirror some features of early embryos, allowing the team to explore the mysteries of early human development. 

Developing the new model 

The neural tube (brown) and somites (pink) are in close communication. Credit: Komal Makwana, Nature Cell Biology.

Described in a study in Nature Cell Biology, Komal Makwana and Louise Tilley in the team used their knowledge of existing systems and adapted experimental methods to produce a new model that self-organises around ten somites alongside a single neural tube. These structures mirrored aspects of human embryos at 28 to 35 days after fertilisation.

“The somites and neural tube develop from certain stem cells at one end of the structures,” explains Komal. “If we facilitate the correct conditions, the structures can spontaneously develop the two tissues, in an organised manner in time and space.” 

The models don’t contain a notochord, a rod-like structure that coordinates tissue development across the middle of the body by secreting signalling factors. This meant that Komal and Louise could test if the somites and neural tube could be altered in a similar way, just by adding a single small molecule at different concentrations. 

“We introduced signals that would have originally come from the notochord, and observed a shift in cell fates. But we also saw spontaneous patterning in the neural tube, showing it was developing into different identities depending on the cell’s location,” explains Komal. “This was fascinating as it suggests that the somite and neural tube cells were communicating with one another.”

The researchers then investigated the signalling landscape within the model, confirming what had previously only been reported in model organisms, including mouse and chicken embryos. This included various important chemical signals in the somites, making sure that cells were assuming the correct identities. 

Two-way communication

The neural tube is shown in red (left) and light pink (right). The somites are shown segmented into different sections in pink and blue (left and right). Credit: Komal Makwana, Nature Cell Biology.

Excluding other embryonic structures from the trunk models allowed the team to decipher messages between the somites and neural tube, which would otherwise be lost in the noise of a more complex model. 

“Surprisingly, a gene involved in processing retinoic acid signalling was found in high concentrations in parts of the somites closest to the neural tube, suggesting that the two structures are in close communication,” says Komal.

The team then confirmed that the increased retinoic acid signalling in specific somite regions was likely due to signalling to the neural tube, and allowing spontaneous patterning. 

“We think this crosstalk helps prompt the regional identities, and might be important for later maturation to neuronal or skeletal tissues,” considers Komal. “The somites are responsible for generating muscles that are critical for posture, locomotion and respiration, so the coordination between these cells and the neurons is critical for the developing embryo.” 

A useful tool for the future

For Naomi, the simplicity of the new model offers promise for future research.

“Problems in this time window of early development can result in pregnancy loss if the body plan doesn’t form fully,” she explains. “And misregulation of these signalling pathways may lead to birth defects. With this system, we can trace how key structures first emerge and interact, illuminating a stage of human development we’ve never been able to watch unfold before.”