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Modelling Downs syndrome using induced Pluripotent Stem Cell (iPSC) derived neural crest cells and


Academic year: 2021

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Modelling Downs syndrome using induced Pluripotent Stem Cell (iPSC) derived neural crest cells and “mini brains”

Sanjay Vasudevan

Every cell in a human body contains a nucleus, which houses genetic material in the form of DNA. These genes are responsible for all the traits that we inherit from our parents. They are stored in structures called chromosomes. Normally, there are 23 pairs of chromosomes present in a nucleus. But in abnormal circumstances, the number of chromosomes present in the nucleus can vary which can cause complex genetic disorders. Downs syndrome is one such genetic disorder. It is one of the most prevalent genetic conditions which affects one in every 750 child births. It occurs when an individual possesses an extra copy of chromosome 21 and hence has three copies instead of a pair. Genes are expressed differently in a normal individual compared to an individual with trisomy 21 (T21). Bridging the gap between a normal and a T21 patient requires understanding the functions and effects of these genes present in developing brains. Since Down syndrome is a neurodevelopmental disorder, it is imperative that the cells formed during early developmental stages are investigated for discrepancies in gene expression. One such cell type is neural crest cell (NCC). Neural crest cells are cells with high migratory characteristics that are involved in the formation of a wide range of tissues. Induced pluripotent cells (iPSCs) are cells that are derived by reprogramming skin or blood cells of an individual (normal or diseased). They have the ability to give rise to any other cell type or lineage by subjecting them to certain biological conditions. When differentiated into desired lineages, iPSCs may reduce the need for obtaining material from humans as well as from animal models that do not fully recapitulate the abnormalities of various disorders. This thesis focuses on developing a reliable method to generate neural crest cells using patient derived induced pluripotent stem cells (iPSCs) and use these cells to study various discrepancies seen in Down syndrome. The neural crest cells generated from normal and T21 iPSCs were characterised successfully, meaning they were checked for authenticity using various methods. They were then subjected to RNA sequencing. RNA-seq is a technique which reveals the quantity of RNA of genes present in the sample. It was done to identify genes which were most differentially expressed in T21 neural crest cells compared to normal neural crest cells and we successfully reproduced a set of genes which are reported to be involved in Down syndrome. Apart from this, we also investigated “mini brains” derived from healthy and T21 iPSC. We found that the T21 “mini brains” had fewer neuron rich regions compared to healthy “mini brains” confirming the fact that neuron composition in Down syndrome is reduced compared to a normal individual.

Degree project in Biology, Master of Science (2 years), 2020 Examensarbete i biologi 60 hp till masterexamen, 2020


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