Funding outcome

KBG syndrome is a rare neurodevelopmental disorder reported in approximately 500 children worldwide. This syndrome is caused by deletions or mutations in the ANKYRIN REPEAT DOMAIN 11 (ANKRD11) gene, which encodes a chromatin remodeler. Chromatin is the condensed structure of genomic DNA that impacts global gene expression, which in turn regulates cell and organism function, including brain development. A critical brain region implicated in neurodevelopmental disorders is the hippocampus, which is essential for learning and memory. It hosts adult neural stem cells, which give rise to adult neurons that can then integrate themselves into previously established neural circuitry and influence hippocampus-dependent learning and memory tasks. While hippocampal structural deficiencies have been recorded in children with KBG syndrome, the role of Ankrd11 in the development and function of the hippocampus is not known. We hypothesize that Ankrd11 is a critical regulator of hippocampal neurogenesis. To test this hypothesis, I will use a KBG syndrome pre-clinical mouse model, where we will remove one copy of Ankrd11 in neural stem cells. The hippocampus will be micro-dissected from the resulting brains and hippocampal neural stem cells will be expanded and allowed to differentiate (transform) into neurons. I will analyze self-renewal, survival, migration and differentiation of control and Ankrd11-deficient neural stem cells. The results of this study will reveal whether Ankrd11 is a critical regulator of hippocampal neural stem cells and provide a foundation for future in vivo experiments. Furthermore, it may also provide a platform for future drug screening experiments to restore abnormal Ankrd11 function or resulting aberrant neural stem cell fates (e.g. proliferation or differentiation).