FOXR1 regulates stress response pathways and is necessary for proper brain development

Area of Science:

• Genetics and Molecular Biology
• Neuroscience
• Developmental Biology

Background:

• Forkhead box (Fox) transcription factors are crucial for cellular and developmental processes.
• FOXR1, a member of the Fox family, has roles in various biological functions.

Purpose of the Study:

• To investigate the impact of a de novo missense variant (M280L) in the FOXR1 gene on neurological function and cellular stress response.
• To elucidate the role of FOXR1 in embryonic brain development.

Main Methods:

• Case study of an individual with severe neurological symptoms.
• Protein analysis to assess the effect of the M280L variant on FOXR1.
• RNA sequencing and pathway analysis to identify FOXR1-regulated genes and pathways.
• CRISPR/Cas9 gene editing in mice to create Foxr1 knockout models.
• Quantitative PCR to assess Foxr1 expression in mouse embryos.

Main Results:

• The M280L variant in FOXR1 leads to impaired protein expression, misfolding, and nuclear aggregation.
• FOXR1 is a key regulator of heat shock response, protein refolding, and cellular stress pathways, directly controlling HSPA6, HSPA1A, and DHRS2.
• The M280L mutant exhibits a compromised ability to respond to cellular stress.
• Foxr1 knockout mice display severe survival deficits, reduced body weight, atypical brain development with decreased cortical thickness, and enlarged ventricles.
• Foxr1 expression is detected in the embryonic brain.

Conclusions:

• The FOXR1 gene plays a critical role in cellular stress response pathways.
• FOXR1 is essential for normal embryonic brain development.
• Disruption of FOXR1 function, as seen with the M280L variant, can lead to severe neurological deficits and developmental abnormalities.