Identifying the downstream targets of neural FOXP1
Project Number1R03MH133952-01A1
Former Number1R03MH133952-01
Contact PI/Project LeaderPEARSON, CAROLINE ALAYNE
Awardee OrganizationWEILL MEDICAL COLL OF CORNELL UNIV
Description
Abstract Text
SUMMARY
FOXP1 syndrome (FOXP1S) is a rare neurodevelopmental disorder causing severe language impairment, motor
delays, visual-motor integration deficits, complex psychiatric presentations, repetitive behaviors, sensory
impairment, and Autism symptoms. The major pathogenicity mechanism is haploinsufficiency and most identified
mutations lie within the DNA binding domain resulting in loss of transcriptional repressor activity. However, the
direct binding targets of FOXP1 in neural cells are yet to be elucidated. Our goal is to further our understanding
of the disease mechanisms underpinning FOXP1S by determining the transcriptional networks regulated by
FOXP1 in human cortical neural progenitor cells (NPCs) and neurons.
In other systems, Foxp1 regulates cell cycle dynamics and differentiation by influencing glucose
homeostasis, metabolism, angiogenesis, and response to hypoxia. FOXP1 has been shown to contribute to
multiple cancers and has been identified as a druggable target as well as a prognostic biomarker. During mouse
and human cortical development, Foxp1 is expressed by NPCs and neurons and several studies have sought to
determine its role in these different cell populations. In NPCs, Foxp1 promotes symmetric divisions, promoting
self-renewal and the generation of early born neurons. In neurons, Foxp1 has been shown to play roles in
neuronal differentiation, migration, and morphology. Whilst it has been classified as a transcriptional repressor,
evidence supports a role for Foxp1 as a transcriptional activator during brain development. Given its expression
in these two distinct cell populations, and our long-term aim to develop an in vitro model of FOXP1S it is important
to determine the cell-type specific targets of human FOXP1.
Our specific aims are to 1) identify the direct binding targets of FOXP1 in human cortical neural
progenitors and neurons and 2) determine the transcriptional changes of direct targets in FOXP1 deficient human
cortical NPCs and neurons. Using wildtype and FOXP1 homozygous mutant human induced pluripotent stem
cells (iPSCs) we will generate cortical NPCs and neurons using the Dual SMAD inhibition directed differentiation
methods. For Aim 1, using CUT&RUN followed by DNA sequencing, we will identify FOXP1 binding motifs in
NPCs and neurons, using FOXP1-/- cells to distinguish genuine peaks from background noise. For Aim 2, we
will perform bulk RNA Sequencing with wildtype and FOXP1-/- iPSC-derived NPCs and neurons to identify the
transcriptional changes of direct target genes (identified in Aim 1) in the absence of FOXP1. This will enable us
to determine whether FOXP1 acts as a transcriptional repressor or activator.
The experiments outlined in this proposal will enable us to address the fundamental role of FOXP1 in
cortical development, and place FOXP1 within transcriptional networks that will inform future studies aimed at
developing a 3D in vitro model of the rare disease FOXP1S and identifying therapeutic targets.
Public Health Relevance Statement
PROJECT NARRATIVE.
Understanding the downstream activities of FOXP1 is critical to our understanding of normal brain development
and the etiology of the rare neurodevelopmental disorder FOXP1 syndrome (FOXP1S). The proposed studies
seek to investigate the direct binding targets of FOXP1 to determine its role in neural progenitor cells and
neurons. Through these studies we will gain novel insights into the disease mechanisms that underpin FOXP1S,
increasing our potential to identify potential therapeutics.
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