Huntingtin hPSC · Unraveling huntingtin function in cortical and striatal human development

Unraveling huntingtin function in cortical and striatal human development

Huntington's disease (HD) is a rare neurodegenerative autosomic dominant disorder which main symptoms include severe motor dysfunction and cognitive deficits. Genetically, HD is a monogenic disorder driven by an expanded CAG repeat mutation located at the 5' end of the huntingtin gene (Htt) that results in increased dysfunction and cell death of striatal medium spiny neurons (SMN) and certain cortical areas. Although HD main symptoms are manifested at mid-life (around 35 years of age), it has been suggested that early neurodevelopmental defects may be present in the patients that could contribute to the late pathology. The huntingtin gene is ubiquitously expressed in all cells and tissues and it has been shown that its complete loss-of-function leads to early embryonic death due to defects in extraembryonic tissue organization. To circumvent this early lethal phenotype and to focus on the brain phenotype, several conditional knock out and heterozygous mouse models have been consequently generated. The specific cellular and molecular role of huntingtin at different stages of cortical development has also been addressed by conditional knock out mouse models that specifically removed huntingtin from the brain, for instance at an early stage, under an early progenitor promoter. However, to date, no studies have addressed and dissected the different roles of the human huntingtin protein in human cortical and striatal development specifically in the progenitor and neuronal populations. The main goal of this project is the generation of new cellular models to study huntingtin (HTT) function during human brain development in specific neuronal subpopulations using reductionist approaches in a purely in vitro setup through the generation of several Htt conditional and full knock out pluripotent stem cell (PSC) lines. The completion of this project would add to the existing field of research new cellular tools to study huntingtin function in human cells in a time and cellular type-specific controlled fashion. This project will shed some light into a long overlooked topic in HD field, which is the developmental role of huntingtin in the brain, specifically in the cortex and striatum, the two areas that are mostly affected in HD patients. Through this work we will test if developmental defects are caused by the specific loss-of-function of Htt in different neuronal populations in early and late stages in 2D and 3D neuronal cultures. The specific objectives of the present project are: 1) The generation of huntingtin full knock out and conditional knock out pluripotent stem cell (PSC) lines 2) Screening of the phenotypes caused by huntingtin loss-of-function 3) Analysis of the transcriptomic changes caused by loss-of-function of huntingtin

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