Neurogenesis, the formation of new neurons, is dependent on neural stem cells (NSCs) in two regions of the adult brain. A portion of NSCs remain as stem cells, while other daughter cells differentiate into neurons and astrocytes that can integrate into the brain. These new neurons are important for learning and memory. Deficiencies in adult neurogenesis have also been linked to neurodegenerative diseases, psychiatric diseases, and developmental diseases. Better understanding of NSCs and their regulation may have enormous therapeutic potential for disease treatment, including fragile X syndrome (FXS). FXS is the single largest genetic contributor to cases of autism. Although autism is a genetically complex disorder that is hard to model, FXS is caused by silencing of a single gene, encoding FMRP. Therefore, the study of fragile X syndrome will likely help us discover treatments relevant for autism. FMRP is a RNA binding protein that represses many mRNA transcripts and has been shown to bind many mRNAs in the brain. Our lab has found that FMRP is an important regulator of adult neurogenesis and that restoring of FMRP in NSCs can rescue hippocampal learning and memory deficits in adult fragile X mice. FMRP has two autosomal paralogs known as Fragile X Related proteins, FXR1 and FXR2. The FXRs are expressed in the same brain regions and can bind many of the same mRNAs. Although they have the potential to regulate FMRP function, the contribution of FXR1 and FXR2 to FXS is largely unknown. Both FMRP and FXR2 regulate neurogenesis and learning, but FXR1 remains largely unstudied. FXR1 is the only fragile X protein that is essential for survival, indicating it importance in developmental processes. FXR1 is linked to other autism-associated proteins, and in humans the Fxr1 gene is located within a region of DNA associated with autism. The goal of this research is to understand the importance of FXR1 in regulating NSCs in the adult brain. Since neurogenesis also has implications in other neurological diseases, as well as learning and memory, study of FXR1 may have larger implications than FXS. The two aims of this study are to: define the role of FXR1 in adult NSCs in cell culture and in the brains of mice (Aim 1) and investigate how FXR1 controls neurogenesis by identifying the mRNAs it regulates (Aim 2). In order to accomplish these goals, Fxr1 conditional deletion mouse lines will be used. NSCs isolated from these mice will be used to compare normal and deletion conditions by assaying for proliferation, differentiation, and cell death. In the brain, NSC fate will be tracked over time. Several gene array technologies will also be used to identify cell signaling pathways altered with Fxr1 deletion. Important mRNA targets will then be screened for their role in neurogenesis. The outcome of this project will elucidate the role of FXR1 in neurogenesis, creating a fuller understanding of its importance in FXS and other neurological diseases.
Adult neurogenesis is important for learning and memory and is dysregulated in many neurological diseases, including fragile X syndrome. This research project aims to explore the role of fragile X related protein 1 (FXR1) in adult neurogenesis, which could lead to novel therapeutic interventions for neurodevelopmental disorders.