A genomic region dedicated exclusively to the formation and regeneration of an organ

The first mutation of the Wingless gene (“without wings”) was found in Drosophila flies, by chance, in the 1970s, specifically in flies that did not have wings, hence its name. Fifteen years after its discovery, this gene was shown to be conserved in mammals, giving rise to the Wnt family of genes. Mutations in Wnt genes can lead to various types of cancer.

The Wnt family of genes, including its founding member Wingless, regulates numerous processes of embryonic development in both insects and mammals. If so, why was the first Wingless mutation found only affecting the wings of flies? This is the question that was asked in the Development and Growth Control laboratory of the Institute for Research in Biomedicine (IRB Barcelona).

Using gene editing techniques such as CRISPR/Cas9, they discovered an evolutionarily conserved genomic region that regulates the expression of the Wingless protein and is exclusively dedicated to wing formation. Through functional studies, the researchers discovered that this regulatory region not only acts to promote wing formation but also regenerates the wing, in case of damage.

The researchers demonstrated that this regulatory region is exclusively involved in the regulation of Wingless expression during wing formation and, through functional studies, discovered in this regulatory region the presence of two highly redundant modules activated by independent signaling pathways.

“What we have discovered in this study is a very robust genetic regulation mechanism that guarantees the correct development of the wing, and this mechanism is consistent with the crucial importance of these structures for insects in general”, explains Dr. Marco Milan, ICREA researcher and head of the Development and Growth Control laboratory, who has led this study. “The development of wings was a huge evolutionary advantage for insects and was what allowed their expansion and diversification,” says Dr. Milan.

Wingless expression (in red) in Drosophila wing primordia in: regenerating (left), developing (center), and tumorigenic (right). (Images: IRB Barcelona. CC BY-NC-ND)

Regeneration and tumors

When an organ is damaged, the damaged cells send signals to surrounding cells to divide and regenerate the organ. The authors of this study have shown that Wingless is also the molecule responsible for signaling healthy cells to divide and regenerate tissue, and that the regulatory region involved in wing formation is also activated in situations of damage to induce Wingless’s expression.

Through functional studies, they demonstrated that the JNK stress signaling pathway acts redundantly on the two existing modules. “Again, a very robust genetic regulation mechanism guarantees not only the correct development of the wing but also its regenerative capacity”, comment Elena Gracia-Latorre and Lidia Pérez, first authors of the study.

Finally, the researchers performed experiments in which they blocked the removal of damaged cells and found that the Wingless regulatory zone remained continuously activated. As a consequence of the constant presence of Wingless, the cells proliferated uncontrollably and eventually gave rise to the formation of tumorous and malignant growths. “This allows us to propose that regeneration and tumor development are two sides of the same coin: if Wingless is induced for a short period of time, it forms the wing normally or allows it to regenerate, but if it is maintained chronically then it it causes an overgrowth and a tumor”, concludes Dr. Milan.

The study is titled “A single WNT enhancer drives specification and regeneration of the Drosophila wing.” And it has been published in the academic journal Nature Communications. (Source: IRB Barcelona)