HomeScience and ResearchScientific ResearchCRISPR-CAS 9 helps identify a missing genetic switch that leads to clubfoot

CRISPR-CAS 9 helps identify a missing genetic switch that leads to clubfoot

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Researchers at UNIGE have found out how not having a certain type of genetic switch can cause problems during embryonic development.

Embryonic development goes through a series of very delicate stages. Many genes must work together to make sure everything works out. This precision mechanism sometimes doesn’t work right, which can cause more or less disabling birth defects.

When researchers looked at the Pitx1 gene, which is one of the genes that play a role in the construction of our lower bodies, they found that a small glitch in the activation process is what causes clubfoot, a common foot birth defect.

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Indeed, even if a gene is fully functional, it can’t work properly without one of its switches. These short DNA sequences are what tells the body to turn DNA into RNA, and they are very important for this process. Switches: When one of these is missing, the percentage of cells with the gene is lower, which stops the lower limbs from being built the way they should be.

These findings, which can be found in the journal Nature Communications, show how genetic switches play a big role in developmental disorders.

During embryonic development, hundreds of genes must be turned on or off just right for organs to grow properly. This control of activity is done by short DNA sequences that, when they bind to proteins in the cell nucleus, act like real switches that can turn on or off the activity.

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“When the switch is turned on, it initiates the transcription of a gene into RNA, which in turn is translated into a protein that can then perform a specific task,” explained professor Guillaume Andrey, the lead author of the study.

“Without this, genes would be continuously switched on or off, and therefore unable to act selectively, in the right place and at the right time.”

In general, each gene has a lot of switches to make sure that the mechanism is strong.

“However, could the loss of one of these switches have consequences? This is what we wanted to test here by taking as a model the Pitx1 gene, whose role in the construction of the lower limbs is well known,” says Raquel Rouco, co-first author of this study.

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Clubfoot is caused by a lack of cellular activity.

To accomplish this, the scientists manipulated mouse stem cells using the genetic editing tool CRISPR-CAS 9, which enables the addition or deletion of specific DNA sequences.

“Here, we removed one of Pitx1’s switches, called Pen, and added a fluorescence marker that allows us to visualise the gene activation,” added Olimpia Bompadre, co-first author.

“These modified cells are then aggregated with mouse embryonic cells for us to study their early stages of development.”

Most of the time, about 90% of the cells that will become the legs turn on the Pitx1 gene, while 10% of the cells don’t.

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“However, when we removed the Pen switch, we found that the proportion of cells that did not activate Pitx1 rose from 10 to 20%, which was enough to modify the construction of the musculoskeletal system and to induce a clubfoot,” added Guillaume Andrey.

As a result: the number of inactive cells rose, especially in the lower limbs and in irregular connective tissue, which is important for building the musculoskeletal system. This is true.

Mechanism

Scientists at UNIGE have found a general principle that could be used to figure out how a lot of genes work. This principle could be used to figure out how a lot of genes work. Flaws in genetic switches could be the source of a wide range of malformations or developmental diseases. A gene doesn’t control the development of just one body part. It’s usually involved in the development of a wide range of body parts.

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“A non-lethal malformation, such as clubfoot, for example, could be an indicator of disorders elsewhere in the body that, while not immediately visible, could be much more dangerous. If we can accurately interpret the action of each mutation, we could not only read the information in the genome to find the root cause of a malformation, but also predict effects in other organs, which would silently develop, in order to intervene as early as possible,” the team concluded.

Source: 10.1038/s41467-021-27492-1

Image Credit: Getty

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