Saturday, May 18, 2024
5/18/2024
Project summary/abstract Autism spectrum disorders (ASD) are estimated to affect 1 in 36 children in the US, yet treatments for ASD remain limited. Mutations in the transcription factor, FOXP1, have been linked to ASD, yet the precise role for Foxp1 in either neurodevelopment or ASD remains incomplete. Previous studies of ASD have also shown that the cortex may exhibit disrupted structure and function. In line with this, we previously created a forebrain specific Foxp1 knockout mouse model and observed that there were behavioral abnormalities including social deficits, communication impairments, and hyperactivity. However, the molecular mechanisms that result from Foxp1 loss in early neocortical development remain unclear. Given the cell-type specific expression pattern of Foxp1 during cortical development, understanding the cell specific function of Foxp1 is critical for the advancement of our understanding of neurodevelopmental disorders. Here, I propose to evaluate the impact of Foxp1 loss on two aspects of early neocortical development: migration and cell fate. First, I hypothesize that Foxp1 loss disrupts radial migration of upper layer neuronal subtypes through their interaction with aRGC fibers. I will test this hypothesis by utilizing 1) BrdU birth dating to track migration of neurons from the VZ along with 2) GFAP staining of aRGC fibers and 3) MERSCOPE’s capacity for detecting up to 1000 cell-type markers at a single time to determine the cell-type specific impact of Foxp1 loss on neuronal migration during upper and lower layer cortical neurogenesis. Concurrently with this, I will also stain for genes identified as downstream targets of Foxp1 through the collection of snRNAseq and CUT&RUN data in order to determine the impact of Foxp1’s downstream targets on migration. Secondly, I hypothesize that Foxp1 loss disrupts the timeline of neurogenesis causing changes in neuronal cell fate. In Aim 2, I will test this hypothesis by leveraging data from Aim 1 to assess the impact of Foxp1 on cell-type and cell fate during canonical upper layer and lower layer neurogenesis. I will do this by comparing the birthtime of a neuron, indicated by BrdU, to its cell-fate after two or after seven days. I will also repeat experiments from Aim 1 during the proliferative and gliogenesis phases of cortical development to determine whether cell fate is altered. By completing these aims and receiving training in the methods needed to generate and analyze these data, I will determine which cell types are most vulnerable to migration and cell fate deficits in a model system relevant to ASD. I will also provide key insights into the mechanisms of neurodevelopment, migration, and cell fate in the developing embryonic cortex. This will ultimately provide a critical foundation for the advancement of precise cell type targeted genetic therapies of neurodevelopmental disorders. Furthermore, I will receive training in cutting edge wet bench technologies, including cellular resolution spatial transcriptomics, CUT&RUN, and snRNAseq while gaining tremendous experience as a bioinformatician. This expertise will enable me to continue to advance our understanding of cell type-specific genetic contributions to development and disease throughout my career.
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