Project Details
Projekt
Actin-dependent mechanisms relevant for cerebellar morphogenesis and medulloblastoma formation
Subject Area
Developmental Neurobiology
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 563584584
Medulloblastomas (MB) are the most common malignant brain tumors in children. SHH-MB, a specific subtype of MB, is caused by pathological activation of the sonic hedgehog (SHH) signaling pathway in cerebellar granule cell progenitors (GCP). Understanding the molecular mechanisms that lead to the physiological maturation of these progenitor cells is therefore an essential prerequisite for the identification of therapeutic targets and the development of drugs for the treatment of children with SHH-MB. Our preliminary data in mice identified the actin-binding protein cyclase-associated protein 1 (CAP1) as a crucial regulator of GCP proliferation and cerebellar development. We have also generated and characterized a genetic mouse model for SHH-MB that is ideally suited for studying the biology and treatment of SHH-MB. In the planned project, we are initially planning in vitro and in vivo experiments on both primary GCP cultures and inducible conditional knockout (KO) mice to elucidate the CAP1-dependent molecular mechanisms relevant for GCP function. This will include gene-targeted mice that allow us to induce and inhibit a transcriptional program controlled by the transcription factor serum response factor (SRF) and its coactivator myocardin-related transcription factor (MRTF), which we found to be controlled by CAP1 and which was dysregulated in GCP from brain-specific CAP1-KO mice. Further, by exploiting our conditional CAP1 KO strain and our SHH-MB mouse model as well as by CAP1 inactivation in patient-derived xenografts for SHH-MB, we will elucidate the role of CAP1 for SHH-MB formation and progression. Finally, we will use cell lines of human SHH-MBs as well as primary and established murine Shh-MB cells for 3D cell culture systems and inhibit and stimulate the CAP1-MRTF-SRF axis to determine the potential of new treatment modalities for children with MB.
DFG Programme
Research Grants
