Balancing Sonic hedgehog Signaling in Health and Disease of the Brain

• Applicant: Dr. Annabel Christ
• Subject Area: Developmental Neurobiology ; Cell Biology
• Term: from 2016 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 326429871

The morphogen sonic hedgehog (SHH) is a central regulator of stem and progenitor cell niches in the embryonic and adult mammalian organism. Its function is essential for proper development and functional integrity of the central nervous system, and defects in this pathway are the cause of devastating developmental abnormalities as well as cancer of the human brain. Because pharmacological intervention with SHH activity has proven highly successful in the clinics, elucidation of the molecular mechanisms of SHH action holds great promise for a better understanding of diseases caused by SHH dysfunction, and for the identification of novel targets for therapy. Towards this overall goal, this proposal will address the functional significance of SHH binding proteins, a novel group of auxiliary cell surface receptors for SHH shown to be essential for proper morphogen function, and to cause severe brain malformations in humans and animal models when defective. Using novel transgenic mouse models as well as advanced organ culture systems of the embryonic and the adult brain, we will elucidate the molecular mechanisms whereby SHH binding proteins regulate morphogen action during brain development and in adult neurogenesis. Investigations in mouse models will be complemented by studies in neuroepithelial cell lines derived from human induced pluripotent stem cells (iPSCs) with genetically engineered human receptor mutations to validate the significance of our findings for the human condition.

• DFG Programme: Research Grants