Identification of disease-relevant modulators of the SHH pathway in the developing brain

Area of Science:

• Developmental Biology
• Genetics
• Molecular Biology

Background:

• Pathogenic variants in the sonic hedgehog (SHH) pathway cause severe brain malformations with variable penetrance.
• The underlying genetic modifiers influencing this variability are largely unknown.

Purpose of the Study:

• To identify modifier genes that influence SHH pathway activity and congenital malformations.
• To characterize the function of novel modifier genes in neurodevelopment and heart development.

Main Methods:

• Generation of congenic mouse models to study genetic modifiers.
• Comparative transcriptomics to identify candidate modifier genes.
• Functional analyses of candidate genes (Pttg1, Ulk4) in mouse models.

Main Results:

• LRP2-deficient mice on a C57BL/6N background exhibit heart and brain defects due to impaired SHH signaling.
• These defects were fully rescued in LRP2-deficient mice on an FVB/N background, indicating strong genetic modulation.
• Pttg1 and Ulk4 were identified as upregulated candidate modifiers in the rescue strain.
• ULK4 and PTTG1 were confirmed as positive regulators of SHH signaling and components of primary cilia.

Conclusions:

• ULK4 and PTTG1 act as crucial positive regulators of SHH signaling, enhancing pathway resilience.
• These genes are novel components of primary cilia, important for neuroepithelial function.
• Understanding these modifiers is key to explaining variability in human congenital disorders affecting brain and heart development.