Project Details
Description
ABSTRACT
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.
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.
Status | Finished |
---|---|
Effective start/end date | 15/9/18 → 30/6/24 |
Links | https://projectreporter.nih.gov/project_info_details.cfm?aid=10837315 |
ASJC Scopus Subject Areas
- Cancer Research
- Genetics
- Oncology
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