Newswise —
Scientists at the Francis Crick Institute, King’s College London, and University College London have illuminated the genetic mechanisms responsible for alterations in the configuration and form of the facial and cranial features in a Down Syndrome mouse model.
Reported in a recently published article in Development, the investigators discovered that an extra copy of the Dyrk1a gene, in conjunction with a minimum of three other genes, were accountable for the occurrence of craniofacial dysmorphology during embryonic development. This condition entails a reduction in the length from the back to the front of the head and an increase in the diameter of the head.
Down Syndrome, which affects 1 in 800 live births, is recognized as a "gene dosage disorder," signifying that it involves alterations in the quantity of gene copies. Individuals with Down Syndrome possess three copies of chromosome 21 instead of the typical two. While having three copies of specific genes on this chromosome causes characteristics typical of Down Syndrome, the exact genes responsible for these features are yet to be identified.
Under the direction of Victor Tybulewicz from the Francis Crick Institute and Elizabeth Fisher from University College London, groups of researchers employed genetic engineering to generate mouse strains with three duplicated regions on mouse chromosome 16, effectively replicating the presence of a third chromosome 21. The mice exhibited many characteristics linked with Down Syndrome, such as modifications in the facial and cranial structure.
Previous research has linked a gene called Dyrk1a to aspects of Down Syndrome, so the researchers wanted to test how it impacted craniofacial dysmorphology.
Collaborating with Jeremy Green's team at King’s College London, the researchers demonstrated that mice possessing an additional copy of Dyrk1a exhibited a decreased number of cells in the bones located at the front of the skull and in the face. Additionally, the cartilaginous joints situated at the skull's base, known as synchondroses, were abnormally fused together. The partial reversal of these effects was observed when the third copy of Dyrk1a was eliminated, indicating that possessing three copies of Dyrk1a is necessary to induce these changes in the skull.
The researchers hypothesize that an additional copy of Dyrk1a interferes with the development of neural crest cells, which are crucial for the formation of bones at the front of the skull.
Apart from Dyrk1a, the study demonstrated that three other genes play a role in the cranial modifications observed in Down Syndrome mice. However, further investigation is required to identify these genes accurately.
Victor Tybulewicz, the head of the Down Syndrome Laboratory at the Crick, who collaborated with first author Yushi Redhead, stated: "Currently, there are only limited treatments available for the health-related aspects of Down Syndrome, such as cognitive impairment and congenital heart conditions. Therefore, it is crucial that we determine the genes responsible for these features."
"Comprehending the genetics underlying the development of the head and face provides us with insight into other aspects of Down Syndrome, such as heart conditions. As Dyrk1a plays a vital role in craniofacial dysmorphology, it is highly probable that it also contributes to other alterations observed in Down Syndrome," added Victor Tybulewicz.
The team at King's College London employed shape-measuring tools to track the changes in the skull shape of the mice. The results revealed alterations in the skull shape that closely resembled those observed in individuals with Down Syndrome.
Jeremy Green, a professor of developmental biology at King's College London, mentioned, "By collaborating with the University of Calgary in Canada and a medical imaging software group at King's, we were able to utilize both conventional and innovative techniques to compare intricate anatomical shapes. These methods were sensitive enough to detect differences even at the fetal stage. This allowed us to identify the locations of genes that lead to Down Syndrome and also gain insight into how these genes cause the observed differences."
This study is part of a continuing initiative to comprehend the genetics of Down Syndrome. The investigators will subsequently endeavor to recognize the genes associated with cardiac abnormalities and cognitive disability, bringing us one stride nearer to comprehending how to devise focused remedies for elements of Down Syndrome that influence well-being.
-ENDS-
The Francis Crick Institute is a biomedical discovery institute dedicated to understanding the fundamental biology underlying health and disease. Its work is helping to understand why disease develops and to translate discoveries into new ways to prevent, diagnose and treat illnesses such as cancer, heart disease, stroke, infections, and neurodegenerative diseases.
An independent organisation, its founding partners are the Medical Research Council (MRC), Cancer Research UK, Wellcome, UCL (University College London), Imperial College London and King’s College London.
The Crick was formed in 2015, and in 2016 it moved into a brand new state-of-the-art building in central London which brings together 1500 scientists and support staff working collaboratively across disciplines, making it the biggest biomedical research facility under a single roof in Europe.
King’s College London’s Faculty of Dentistry, Oral & Craniofacial Sciences is one of the foremost dental schools in the world. Recently rated in the top ten in the world in dentistry by the QS World University Rankings 2023, the Faculty aims to maximise impact on health and wellbeing by integrating excellence across four areas:
- Education / teaching
- World-class science
- Clinical approaches
- Patient care
The Faculty’s mission is to understand disease, enhance health and restore function. Their vision is to be world leading in dental, oral and craniofacial education, research and clinical care.
The Faculty’s international reputation attracts students and staff from across the globe. The largest dental academic centre in the UK, they teach over 700 undergraduate students, 140 graduate taught students, 300 distance learning students and 110 graduate research students. The Faculty is shaped by a diverse student and staff population which adds strength to its standing.
The faculty has over 85 academic staff and is organised into three research priority areas:
- Development, Regeneration, Repair & Tissue Engineering
- Immunity, Infection & Host-Microbe Interactions
- Clinical, Translational & Population Health.
The research areas complement the teaching and clinical service initiatives.
As well as excellent research facilities, the Faculty has internationally recognised education programmes. With highly skilled teachers and supervisors, there are exceptional facilities, including access to over 300,000 patients each year across world-famous hospitals, Guy’s & St Thomas’, and King’s College Hospitals for hands-on clinical training. They are one of the most comprehensive dental academic health science centres in Europe.
Further details of the faculty may be found on its website: www.kcl.ac.uk/dentistry
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