Date of Award

Spring 2021

Document Type


Degree Name

Doctor of Philosophy (PhD)



First Advisor

Vaccarino, Flora


Ventral telencephalic development gives rise to the basal ganglia, a subpallial brain region responsible for motor function and coordination. This brain region is implicated in many movement disorders, including Tourette Syndrome (TS). TS is a heterogenous neurodevelopmental disorder and its etiopathophysiology is unknown. To date, TS has been investigated in animal models and postnatal human subjects, but early development of this disorder has not been studied. Previous work in adult TS post mortem basal ganglia tissue has shown a reduction in striatal interneurons, which serve to largely regulate striatal output. However, possible mechanisms for this neuronal loss and whether or not these findings originate in early development are poorly understood. This study examines TS etiology by modeling basal ganglia development in tridimensional human induced pluripotent stem cell-derived neural organoids. Basal ganglia organoids were generated from and compared across healthy unaffected control individuals and adult unremitting TS patients. We found early telencephalic patterning disruptions in TS-derived basal ganglia organoids, showing a preference for dorsal-posterior specification instead of the expected ventral-anterior commitment seen in healthy control-derived organoids. The aberrant fate shift in the TS-derived basal ganglia organoids was seen at both RNA and protein levels, confirmed across three separate assays, with consistency across three distinct time points. Transcriptome analyses in the organoids further identified categories of neuronal deficits that show overlap with a manually curated list of differentially expressed genes uncovered by transcriptome analyses at the post mortem level, reiterating the relevance of the bioassay utilized in this study. This work also investigated a potential mechanism for the early developmental phenotypes observed in the TS organoids. We found significant alterations in sonic hedgehog (SHH) signaling components at both RNA and protein levels that are essential for distinguishing dorsal-ventral patterning in the human brain. Additionally, transcriptome analyses reveal a potential role for cilia, the cellular protrusions that facilitate SHH signal transduction. We found disruptions in genes that are required for cilia formation and function in the TS basal ganglia organoids that were absent from the healthy controls. This study leads an early developmental examination of TS in humans and offers a bioassay applicable to modeling basal ganglia-related disorders. These results reveal new biomarkers of interest in TS etiology and describe a new implication for SHH signaling. These results indicate that TS patients may exhibit altered telencephalic development, which yields deficits in neurons that ultimately populate the basal ganglia and regulate optimal circuitry function.