2023-06-15 15:15:09
A new study reveals previously unknown genetic aspects of the genetic network that underpins the formation of the eye.
The authors of the study, from the Andalusian Center for Development Biology (CABD), dependent on the Higher Council for Scientific Research (CSIC) of Spain, and other entities, have revealed that the genetic network that sustains the formation of the retina of the eye is resilient to mutations that occur in the process. The discovery helps to understand the genetic mechanisms that guarantee the robust functioning of embryonic development, specifically, the formation of organs in the face of possible occasional mutations of some of its components.
“The eyes of all vertebrates, whether we are talking about a fish, a frog, a bird or a human being, are constructed in much the same way in the developing embryo. This is because the instructions for its formation depend on a network of genes that has been conserved over hundreds of millions of years of evolution of the species”, explains researcher Juan Ramón Martínez Morales, from the CABD.
A handful of master genes control the activation of this network and therefore trigger the formation of the eye in the embryo. In the CABD laboratory, they are focused on understanding the function of some of these master genes, the transcription factors Vsx1 and Vsx2, whose mutation results in congenital blindness in both humans and mice. Their lack of function leads during early fetal development to severe malformations of the eye (known as microphthalmia; that is, small eye), later preventing the generation of a type of neuron that is essential for retinal function, bipolar cells. .
Artist’s impression of a human eye with DNA underneath. (Illustration: Amazings/NCYT)
robust operation
“In this work we have studied the function of the Vsx genes in the formation of the visual system in fish, to understand to what extent its role is conserved in all vertebrates”, indicates the researcher Joaquín Letelier. To do this, they have generated mutant animals using the CRISPR/Cas9 genome editing tool in two evolutionarily very distant fish models (around 200 million years): the zebrafish and the medaka fish. The work demonstrated that, as in humans, the Vsx genes play an essential role in the differentiation of retinal bipolar cells in fish, causing blindness in fish when these Vsx genes are mutated.
However, despite what was previously described in humans and mice, they did not detect early malformations (microphthalmia) in the retina of zebrafish mutants. To delve into this phenomenon, they created molecular analyses, which revealed a scenario of genetic redundancy, in which the mutation of a master gene (no matter how important it is individually), is not enough to prevent the activation of the entire network and therefore the formation of the eyes in this species.
“This work has not only allowed us to generate animal models that will allow us to delve into the function of the Vsx1 and Vsx2 transcription factors, but also exemplifies a transcendental principle in biology: the principle of functional redundancy. As occurs in the famous game Jenga, the elimination of a central block of the genetic tower that sustains the formation of the eyes seems insufficient for the entire program to fall apart”, concludes the researcher Martínez Morales.
This work, therefore, helps to understand the genetic mechanisms that guarantee the robust functioning of development programs, and therefore the formation of organs, in the face of possible occasional mutations of some of their components. In living organisms, at all their organization scales, this principle of functional redundancy works, in which each process is screwed together simultaneously by mechanisms that work in parallel. “To use an simile, it is the same as going with suspenders and a belt: if one fails, the other continues to act and does not allow the pants to drop (or there are defects in the eyes, in this case)”, he concludes.
The work shows that the regulatory weight of the Vsx genes varies substantially between vertebrate species, focusing on gene redundancy as a basic mechanism to maintain the robustness of the retinal development program throughout the animal group. This information is important to understand the etiology of the most common congenital ocular malformations, such as microphthalmia, anophthalmia, and coloboma, which are the origin of the most common congenital blindness in humans. Molecular diagnosis, and perhaps future therapy for this type of malformation, depends on our ability to decipher the architecture of the genetic networks that direct the formation of the retina in the developing embryo.
The study is titled “Mutation of vsx genes in zebrafish highlights the robustness of the retinal specification network”. And it has been published in the academic journal Elife Sciences. (Source: CSIC)
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