This study aims to investigate the role of FOXG1 in neurodevelopment and disease. The forkhead box G1 protein, encoded by FOXG1, acts as a transcriptional repressor primarily expressed within the brain. It is essential for the development of the forebrain and forebrain derived structures. Furthermore, fine-tuned FOXG1 levels are essential for balancing excitatory and inhibitory neuron populations. Loss-of-function (LoF) of FOXG1 is associated with FOXG1 syndrome (MIM #613454), an autosomal dominant disorder characterized by severe developmental delay/intellectual disability, impairment of postnatal growth, absent language, microcephaly, epilepsy, stereotypies, abnormal sleep patterns and structural brain deficits.

Unfortunately, the exact mechanisms impaired during neuronal development in individuals with FOXG1 syndrome are still not well understood & there is no cure available. Since we have induced pluripotent stem cells (iPSCs) available with FOXG1 aberrations, introduced a reproducible protocol for the culture of neural organoids and established an interdisciplinary research team, we are in the unique opportunity to advance our understanding in these areas.

Hence, firstly, using wild type neural organoids, we will unravel the function of FOXG1 during early neural development. Secondly, we will determine the effect of FOXG1 LoF and thirdly, we will assess the therapy potential of RNA activation for FOXG1 syndrome using both wild type and FOXG1 LoF neural organoids.

Overall, the results of this study will deepen our understanding of FOXG1’s role in neurodevelopment and disease, define a consistent pipeline for mixed-method organoid analysis of neurodevelopmental disorders, and may contribute to the development of novel therapeutic approaches for FOXG1 syndrome.