By: Indulekha M S
What happens if the level of a certain protein in your body is reduced by half? Could this alter how your face, brain, and even your heart develop? This is what happens in Rubinstein-Taybi syndrome (RSTS), where a baby is born with unusual facial features, intellectual disability, heart defects, and other traits. It affects about one in 100,000 people, and no treatment is currently available.
RSTS is caused by mutations in the proteins CREBBP and EP300, causing a variety of defects in various tissues. Until recently, it was not known how the loss of these genes led to the defects seen in the patients. The hint came from the types of tissues affected. Many of them develop from a special group of cells called the neural crest cells (NCC). The NCCs originate at the tip of the developing neural tube along its entire length and migrate throughout the embryo to develop into a variety of tissues, including the pigment cells, bones and cartilages on your face, some tissues in the heart, and the nervous system of the gut. These are the very tissues affected in RSTS and this could mean that this disease is linked to defects in the neural crest cells. Shweta Verma and team from Dr. Chetana Sachidanandan’s lab at the CSIR-IGIB decided to test this idea: did the loss of CREBBP and EP300 from NCCs result in RSTS-like phenotypes?
The team decided to look at neural crest development in CREBBP and EP300 mutant zebrafish embryos and compare it to normal NCC development. They used chemicals to block the CREBBP and EP300 proteins and found that such embryos had a delay in neural crest development and migration. It is important for the NCCs to move to the right places at the right time to differentiate. A defect in this cell migration could also mean that the differentiated tissues are affected. When they looked at the tissues derived from NCCs, they found that these were indeed affected in different ways.
Now, how do these proteins control neural crest migration? When an embryo develops, the neural crest cells detach from the neural tube in a process called delamination. After delamination, the cells migrate to specific areas and later differentiate. This step requires an inhibition in the cadherin 6 protein levels. Shweta and team found that, in the mutants, the level of this particular gene stays high and the cells don’t detach properly leading to delays in their migration.
But all this was shown in fish. Does this truly reflect what happens in humans who suffer from RSTS? To test this, they used stem cells derived from human RSTS patients, differentiated them into NCCs, and checked their ability to migrate. Just like in the zebrafish model of the disease, the NCCs derived from patients who suffered from RSTS had defects in migration. This strongly suggests that what the fish model of the disease tells us is likely true: the defects seen in RSTS are due to migratory defects in NCCs caused by a reduction in the levels of CREBBP and EP300.
Since many of our tissues develop from the NCCs, abnormalities in these cells account for a large proportion of birth defects. In India, more than 1.7 million children are born with many such issues at birth. Studies such as these are among the various approaches necessary to understand how these disorders occur so that we can move toward their prevention and management.
Read the full paper here: https://www.biorxiv.org/content/10.1101/2024.05.19.593474v1
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