A research team studies the role morphogens play in tissue patterning in cardiac development

Morphogens are molecules that move from one biological cell to another to shape the tissues of the embryo. These molecules are important not only for the embryo during its development, but also for the adult during tissue repair. However, how these morphogens are distributed to provide patterning is not yet fully understood.

Using a combination of experiments and mathematical modelling, a research team from the University of Tokyo and their international collaborators have learned more about the role morphogens play in tissue patterning. The results are relevant for medical applications, such as drug design. The team’s findings are published in the journal eLife.

The Wnt morphogen has emerged as a key regulator of cardiac development in vertebrates. These Wnt proteins are molecules that play an important role in cell development. However, scientists still don’t know exactly how Wnt regulates heart development. There are differences between classes of vertebrates, as well as redundancy in some species. However, scientists can study how Wnt regulates cardiac development in the Xenopus, an aquatic frog native to sub-Saharan Africa. The Xenopuswith its lungs and three-chambered heart, is cost effective and useful to scientists in their study of human disease.

In Xenopus heart development, scientists have already established that the morphogen Wnt6 is sent by the epidermis, those outer layers of cells that make up the skin, to mold the cardiogenic mesoderm, which is the group of cells in the embryo that will form the heart. From this pattern, a relatively thin pericardium (the membrane surrounding the heart) and a wide myocardium (the muscle tissue of the heart) develop. Scientists are still working to better understand how the distribution of the Wnt6 morphogen is regulated to ensure reproducible positioning of the pericardium and myocardium in the cardiogenic mesoderm. “It is still unclear how reproducible patterning can be achieved with diffusing molecules, especially when this patterning relates to thin tissue differentiation.” said Takayoshi Yamamoto, assistant professor at the University of Tokyo and first author and correspondent on the article.

Scientists know that during early embryonic development, the Wnt8 morphogen signaling range is fine-tuned by heparan sulfate and secreted Wnt-binding proteins, including Frzb (which is also known as sFRP3) . Heparan sulfate is an important carbohydrate for embryo development. Wnt signaling is one of the main processes by which tissues take shape during embryo development. The research team wondered if mechanisms similar to those operating in early embryos also regulate the distribution of the Wnt6 morphogen in the cardiogenic mesoderm.

The Wnt receptor, Frizzled7, is essential for heart development. Frizzled7 expression is increased by Wnt signaling in the developing nervous system in the Xenopus and in developing human embryonic carcinoma cells, but there are no such reports in cardiac development. The research team therefore focused their study on analyzing how Wnt signaling occurs in the developing heart, focusing on extracellular components – the Frizzled7 cell surface receptor, sFRP1 (an inhibitor of Wnt6 which can also travel from cell to cell) and heparan sulfate.

“Through a combination of experiments and mathematical modeling, this receptor feedback appears essential in shaping a steep gradient of Wnt signaling. Additionally, computer simulation revealed that this feedback confers robustness to variations in Wnt ligand production. and allows the system to reach a state quickly,” Yamamoto said.

Wnt6 and sFRP1 molecules not only regulate normal embryonic heart development, but also regulate repair and regeneration after heart muscle damage, such as in the case of myocardial infarction or heart attack. “Our findings will be relevant for medical applications, for example for drug design, because cell surface molecules such as Frizzled or a specific modification of heparan sulfate or even the secreted molecule sFRP1, generally provide better drug targets than molecules inside cells reveal the precise regulation of morphogens and to consider medical applications, the regulatory mechanisms of these components need to be further investigated,” Yamamoto said.

The research was carried out in collaboration with researchers from the University of Aberdeen in the UK

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Materials provided by University of Tokyo. Note: Content may be edited for style and length.

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