The development of the human brain depends on genes being switched on and off with remarkable precision as stem cells mature into neurons. A key regulator of this process is the transcription factor PHF3, which the Slade lab previously identified as a driver of neuronal gene expression. Mutations in PHF3 have been linked to neurological disorders, including microcephaly and autism spectrum disorder, yet the molecular mechanisms underlying these diseases remain poorly understood. “Our goal is to understand how disease-associated PHF3 mutations disrupt the molecular programs that drive neuronal differentiation,” says group leader Dea Slade. To answer this question, the team will introduce patient-derived PHF3 mutations into human induced pluripotent stem cells using CRISPR/Cas9 and investigate their effects in 2D and 3D models of human neuronal development.
Combining genomic, proteomic, and functional analyses, the project aims to reveal how these mutations alter gene expression and ultimately impair neuronal function. The work will be carried out in collaboration with Ruth Drdla-Schutting (Medical University of Vienna) and Gaia Novarino (ISTA), whose groups contribute expertise in patch-clamp electrophysiology and calcium imaging to assess neuronal activity.