Adolescence is a period full of changes that prepare us for adulthood, and in insects, this stage corresponds to a specific phase of metamorphosis: the pupa. But how does the organism know when to leave adolescence behind and move on to its adult form? Previous research suggested that the development of insects is regulated by three main genes that act sequentially: Chinmo, which maintains the juvenile state; Broad, which allows the transition to the adolescent phase; and E93, which leads to adulthood.

Now, a study led by the Institute of Evolutionary Biology (IBE), a joint center of the Spanish National Research Council (CSIC) and Pompeu Fabra University (UPF), has revealed the genetic mechanism that controls the transition from adolescence to adulthood in insects. Until now, it was believed that the E93 gene was primarily responsible for initiating the adult phase, but the research, published in PNAS, has shown that this process cannot begin until the Broad gene, which regulates adolescence, is inactivated.

"We have discovered that, for E93 to induce the transition to adulthood, it is first necessary to eliminate the presence of Broad, something that, interestingly, is done by E93 itself," explains Josefa Cruz, researcher in the Developmental Biology and Evolution group at IBE and the study's lead author. This discovery has been particularly important for understanding the development of a key organ for many insects: wings. The individual must "let go" of adolescence to unfurl them and begin to fly. "We could say that Broad is the 'Peter Pan' gene, as it induces and keeps the insect in an intermediate phase between the juvenile and adult stages, giving time for the organs to develop properly before the transition to adulthood," adds Cruz.

A key genetic triad for cancer research

This study, published in PNAS, not only delves into the genetic mechanism of insect metamorphosis but could also have implications for research on human puberty and cancer. The genes Chinmo, Broad, and E93, essential in regulating the temporal development of insects, have homologs in humans that play a key role in cancer processes. While Chinmo acts as an oncogenic precursor, promoting cell growth and preventing differentiation, Broad and E93 function as tumor suppressors, limiting uncontrolled proliferation and promoting cellular maturation.

The development of insects and humans can be divided into three equivalent stages: larval, pupal, and adult phases in insects—represented in the fruit fly model (Drosophila melanogaster)—and infancy, puberty, and adulthood in humans. The identity of each developmental stage in insects is regulated by the sequential expression of the temporal factors Chinmo, Broad, and E93. In the absence of the adult specifier E93, the pupa cannot complete the transition to the adult stage and remains in the pupal state. Credit: Josefa Cruz, Xavier Franch, and David Martín.

"Cancer cells that form tumors are deregulated cells that retain a more juvenile and plastic identity, allowing them to divide rapidly," explains Xavier Franch, principal investigator at IBE and co-author of the study. "Genetically, these cells are in a state similar to the juvenile stage of insects, where Chinmo promotes accelerated tissue growth. In contrast, puberty marks the beginning of cellular differentiation and, therefore, the end of proliferation."

The advancement in understanding these genetic mechanisms opens new avenues for cancer therapy research, based on the modulation of cell division and differentiation processes. "In breast cancer, for example, it has been observed that activation of the LCoR gene – the homolog of E93, the adult stage specifier – in tumor cells halts proliferation," adds Franch.

The role of Broad in evolution: key to the success of insects

The study reveals that the Broad gene was fundamental in the evolution of complete metamorphosis in insects, a key innovation that has enabled their extraordinary diversification. 80% of the described insect species and 65% of all animal species exhibit this type of metamorphosis.

"Insects with simple metamorphosis, such as cockroaches, go directly from the juvenile to the adult stage, and Broad does not play a significant role in them. In contrast, in insects with complete metamorphosis, this gene has been essential in establishing the pupal stage, making a much more complex metamorphic development possible," explains David Martín, principal investigator at IBE and co-author of the study. According to Martín, "the interaction between the genes E93 and Broad has been crucial for the origin of this intermediate phase – the adolescence of insects – a decisive factor in their evolutionary success."

This discovery could also offer new perspectives on human evolution. "Humans are neotenic animals; we retain juvenile traits into adulthood, such as the shape of the skull, which resembles that of children. In this sense, we are the 'Peter Pans' of the hominids, and understanding how genes regulate cellular plasticity during adolescence in other organisms could help us better understand what defines us as a species," concludes Cruz.

The study was funded by PID2021-125661NB-I00 MICIU/AEI/10.13039/501100011033 and the EU's FEDER fund, as well as the Research and Universities Department of the Government of Catalonia (SGR 00417), among others.

Referenced article: 

J. Cruz, E. Ureña, L.P. Iñiguez, M. Irimia, X. Franch-Marro, & D. Martín, E93 controls adult differentiation by repressing broad in Drosophila, Proc. Natl. Acad. Sci. U.S.A. 121 (51) e2403162121, https://doi.org/10.1073/pnas.2403162121 (2024).