Morphogen receptor LRP2 in heart development and congenital heart disease

• Applicant: Professor Dr. Thomas E. Willnow, since 3/2023
• Subject Area: Developmental Biology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 420380317

The LDL receptor-related protein 2 (LRP2) is an auxiliary receptor essential for signaling of the morphogen sonic hedgehog (SHH) during brain development. LRP2 mutations in patients with autosomal recessive Donnai-Barrow syndrome result in defects in SHH-dependent patterning of the embryonic CNS, and in severe craniofacial and forebrain malformations, a defect known as holoprosencephaly (HPE). HPE is the most common forebrain anomaly in humans. It is also seen in mouse models with targeted Lrp2 disruption, documenting the relevance of mouse models to study the human LRP2 condition. Intriguingly, recent studies in patients and mouse models now have also uncovered LRP2 defects as the cause of malformations of the cardiac outflow tract that normally separates the aorta from the trunk of the pulmonary artery. Conotruncal malformations are detrimental conditions resulting in low oxygen supply to the systemic circulation of affected individuals. They account for 30% of all congenital heart defects in humans (1% of live births), testifying to the clinical importance of this morphogenic event, and the as yet unexplained contribution of LRP2 to this process. In the present proposal, we will use LRP2-deficient mouse models, as well as organ explant cultures derived thereof, to elucidate the molecular mechanism of LRP2 in heart development, and why receptor dysfunction causes septation defects. Our studies will provide important insights into the molecular causes of congenital heart disease and further define the role of LRP2 as genetic cause of devastating inborn errors of human development.

• DFG Programme: Research Grants
• Ehemalige Antragstellerin: Dr. Annabel Christ, until 2/2023