PROJECT SUMMARY/ABSTRACT
Mutations of FOXP1 and FOXP2, which encode forkhead box transcription factors, are associated with autism,
mental retardation and language impairment. Functional studies in animal models have demonstrated
combinatorial roles of FoxPs in the development of the CNS, particularly the forebrain. However, a clear
understanding about their functional mechanisms is lacking. We recently discovered that molecularly
heterogeneous populations of Purkinje cells (PCs) express different combinations of Foxp1, 2 and 4 in the mouse
embryonic cerebellum. Through cerebellum-specific knockout experiments, we showed that the loss of Foxp1 or
Foxp2 impacted PC diversification. Strikingly, deleting both Foxp1 and 2 resulted in a total loss of the cerebellar
hemisphere, which has evolved de novo in mammals and is involved in cognitive and language functions. Our
long-term goal is to determine the molecular and cellular mechanisms underlying the assembly of cerebellar
circuitry. We hypothesize that Foxp1 and Foxp2 cooperatively specify the molecular identity of PC groups
that are crucial for cerebellar hemisphere formation and expansion. To address this hypothesis and
contribute to our goal, we propose to: 1) use single-cell transcriptomics and light-sheet volume imaging to
ascertain how Foxp1 and Foxp2 regulate PC differentiation and morphogenesis of the cerebellum, 2) determine
genome-wide binding profiles of Foxp1 and Foxp2 in mutant and control cerebella. Integrative analysis of data
generated from these aims will unravel the transcription network governed by the combinatorial function of Foxp1
and Foxp2 in the developing cerebellum.
The proposed training plan is sponsored by Dr. Yuanhao James Li and Dr. Justin Cotney at the University of
Connecticut Health Center. The overall goal of the training plan is to provide the PI, Ms. Nagham Khouri Farah,
with a solid foundation for a successful career as an independent scientist. The training plan will help the PI gain
experiences: 1) to conduct multi-omics experiments and analyses, 2) to responsibly conduct research, 3) to
collaborate with other scientists, 4) to present data in a written and oral format, 5) to make a significant
contribution to the science community in the field of genetics, neuroscience and developmental biology.