• AsiaBiotechLive Reporter

Research on mice leads to possible solutions for congenital diseases

Researchers at Duke-NUS Medical School and National Heart Research Institute have discovered key factors that cause head and face abnormalities in mice. These findings may be relevant in uncovering new treatment strategies for human diseases.


Researchers at Duke-NUS Medical School and National Heart Research Institute have discovered important processes that occur in mice which can lead to head and face abnormalities caused by birth defects. Cleft lip and/or palate, characterised by an opening or split in the upper lip and/or palate, is one of the most common birth defects—it occurs in approximately 2 out of every 1,000 live births in Singapore, contributing to one-third of congenital diseases (diseases present since birth).

The lip and palate are tissues formed from neural crest cells in the embryo. In normal cases, these cells have genes that code for proteins involved in many different cellular activities. For example, they enable gene expression, package DNA inside cells and splice (join) different pieces of genetic code to build other proteins. Without these genes, development of the cells will be impeded. This in turn may cause cleft lips or palates.

“Genetic defects that affect neural crest cell generation, migration, proliferation, or differentiation result in cardio-craniofacial malformations, including cleft lip and cleft

palate,” Assistant Professor Manvendra Singh, the study’s corresponding author from the Cardiovascular and Metabolic Disorders Programme at Duke-NUS Medical School, Singapore, explained. (Craniofacial refers to parts of the human body that are within the upper portion of the skull—above the jawbone–as well as the face.) “However, the role of splicing factors during neural crest cell development remained unclear. Our study set out to investigate this so as to better understand the process that leads to these birth defects.”

Splicing factors are crucial protein components of the gene proofreading or ‘splicing’ mechanism found in all cells. Neural crest cells from mice produce a splicing factor called Rbfox2, which controls the expression of genes important for the development of neural crest and craniofacial areas. The research team found that the removal of this gene from the mice resulted in cleft palates and abnormalities in the bones of their head and face.

After more in-depth study, the research team discovered what the genetic code spliced by Rbfox2 is, as well as the effects of splicing events on gene activity in mouse tissues formed from cranial neural crest cells. They also found that a signaling pathway linked to a cell-signaling protein, transforming growth factor-beta (TGF-b), was impaired in the cells lacking Rbfox2. TGF-b is a protein essential to the regulation of cell growth, differentiation (the process by which dividing cells change their functional or phenotypical type) and development in a large range of biological systems.

The damaged signaling pathway forced cells to produce excessive amounts of Tak1, one of the proteins involved in the TGF-b pathway, which mitigated the irregularities resulted from the lack of Rbfox2. It was also deduced that it performs its functions after Rbfox2 does—it acts downstream of the splicing regulator.

The researchers also found another protein involved in the TGF-b signaling pathway. This protein increased the amount of Rbfox2 produced by the neural crest cells after the removal of the protein component by the researchers, making it a positive feedback loop. As altered TGF-b signaling is a prevalent phenomenon among humans who suffer from birth defects, these findings can be pertinent to human disease studies.

“Fundamental research is a vital component of new discoveries in medicine and healthcare. Understanding the molecular mechanism underlying craniofacial and cardiovascular abnormalities helps us to better understand the aetiology of these congenital diseases, with a view to discovering new treatment possibilities,” said Professor Patrick Casey, Senior Vice Dean for Research at Duke-NUS.

“The neural crest is an interesting embryonic cell population as they contribute to a wide variety of derivatives, including the formation and separation of the cardiac outflow tract, as well as patterning and remodeling of aortic arch arteries,” Asst Prof Singh stated. “Our future work in this direction will help to understand the transcriptional network underlying the congenital and cardiovascular defects.”

The research paper was published in June 2019 on eLife.

This article was contributed by Ling Yi, an editorial intern at World Scientific Publishing Co. and a contributing writer for Asia-Pacific Biotech News. She is from Nanyang Girls' High School, has keen interest in learning more about life sciences and exploring literature, in both English and Chinese. She also enjoys studying different languages such as Japanese and Korean, and has a passion for dancing and reading. 

Copyright© 2020 World Scientific Publishing Co Pte Ltd

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