We propose to study the role of the exon junction complex (EJC) in cerebellar development and medulloblastoma. Medulloblastoma is the most common malignant brain tumor in children, and it arises as a disruption of postnatal cerebellar neurogenesis. We have found that neural progenitors in the postnatal cerebellum strictly require EJC function, as genetic deletion of the EJC component Magoh induces catastrophic DNA damage and cell death specifically in these cells. We developed mice in which Magoh could be deleted with temporal control, and found that Magoh deletion causes cell death throughout the cerebellar progenitor population within 72 hours. Moreover, we raised medulloblastoma-prone mice in which Magoh could be deleted with temporal control and found the Magoh deletion in tumors caused DNA damage and cell death similar to the effect in progenitor cells. Based on these findings, we propose that the EJC plays a central, previously unappreciated role in maintaining the genomic integrity and the survival of cerebellar progenitors and medulloblastoma cells. Uncovering the mechanisms through which the EJC regulates progenitors and medulloblastoma cells will provide new insight into the pathogenesis of brain growth failure in microcephaly and may lead to new treatments for medulloblastoma.
Aim 1 of the grant will focus on cerebellar progenitors and use Magoh deletion to identify the mechanisms of DNA integrity and cell survival that depend on the EJC.
Aim 2 will use Magoh deletion to determine how EJC disruption alters tumor growth in a primary, in vivo mouse model of medulloblastoma.
These Aims will show how the EJC maintains progenitor survival during brain growth and test the hypothesis that the EJC can be targeted to improve medulloblastoma therapy.
The results of this project will be directly relevant to microcephaly and other disorders of brain growth, and to the treatment of medulloblastoma, the most common malignant brain tumor in children. Medulloblastomas arise from cells that divide during normal brain growth and use many of the same control systems as these normal cells. This project will investigate why normal cells that divide during brain growth require a gene called Magoh to prevent DNA damage and cell death, and test the hypothesis that Magoh also controls cell survival in medulloblastoma cells. The proposed studies will disrupt Magoh in normal mice, to find the causes of the resulting brain growth failure, and then disrupt Magoh in mice with medulloblastoma, to see if tumor growth is blocked. The results will provide new information about the normal control of brain growth, how this control fails in microcephaly, and whether these control systems can be targeted for brain tumor therapy.
