Induced pluripotent stem cells for modeling of Rett Syndrome

Abstract

Abstract Rett Syndrome (RTT) is an X-linked dominant neurodevelopmental disorder which specifically affecting females. Majority of the cases of RTT is caused because of mutation in methyl-CpG-binding protein (MECP2) gene; besides few cases are caused because of mutation in CDKL5 and FOXG1 gene as well. Since the RTT is a severe disorder and MECP2 and CDKL5 are X linked disorder, therefore, only females are affected. Since, males are hemizygous for X chromosome, therefore, males could not survive with these mutations. In contrast, RTT in males is because of mutations in FOXG1 gene, an autosomal gene. Microcephaly is the prominent phenotype among Rett patients characterized by progressive loss of intellectual functioning, development of stereotypic hand movement, seizures etc. To study the disease pathogenesis, live patients’ neurons are the best suited model system, however, getting patients live brain cells are impossible from an affected individual and also ethically not permissible. Therefore, development of a model system to recapitulate the phenotype of the syndrome with same genome as that of patient is essential. This can be done by using induced pluripotent stem cells (iPSCs) techniques. The main advantage of iPSCs is that it can be used to generate any type of brain cells, even a miniature brain organoid called cerebral organoid can also be generated which can be used to study cross talk between genes and their effects on different brain tissues. The first iPSCs model for Rett was developed by Ellis group in 2009. Subsequently, various researchers successfully generated Rett-iPSCs to evaluate different mutations pertaining to Rett phenotypes. The neurons differentiated from patient-specific iPSCs exhibits similar phenotypes as that of the patients, like reduced soma and nuclear size, decreased dendritic spine density, fewer synapse, altered calcium signaling, etc. It was demonstrated through iPSCs that there is overexpression of GABAergic gene products with MECP2 mutant iPSC-derived neurons while reduced functional synaptic contact and impaired neuronal activity were demonstrated in CDKL5 mutant iPSCs-derived neurons. Moreover, iPSCs-derived neurons from FOXG1-mutated patients showed increased level of GRID1 mRNA levels that regulate synaptic differentiation and thus have altered effect on normal development. Besides the disease pathogenesis study, efforts are also on for cellular therapy as well as evaluating different drug candidates. With the help of latest gene editing technique CRISPR/Cas9, various groups are trying to restore the functionality of MECP2 gene which can lead to a promising way toward treatment for Rett. This technique of iPSCs will be helpful not only for studying RTT in depth but also can pave a path toward drug development to ease the quality of life of the affected children.