DS-01 * GLUCOCORTICOIDS POTENTLY INDUCE APOPTOSIS IN THE CEREBELLAR EXTERNAL GRANULE LAYER: IMPLICATIONS FOR MEDULLOBLASTOMA TREATMENT

Abstract

Premature infants suffering from respiratory dysfunction are often administered glucocorticoids (GCs) to mature the lungs. Unfortunately, neonates exposed to GCs can exhibit neuromotor deficits and selective cerebellar stunting. In order to test the safety of GCs, we administered the synthetic GC dexamethasone to neonatal mouse pups and found it potently increased apoptosis in the external granule layer (EGL) of the cerebellum. The EGL is responsible for producing over 90% of the neurons in the cerebellum, which represents over half the neurons in the entire brain. We subsequently discovered that endogenous GC release, receptors, and enzymatic metabolism is carefully orchestrated to selectively increase stimulation in the EGL as it is naturally eliminated. This suggests the GC system may signal the permanent disappearance of the EGL during development. Unfortunately, EGL neural progenitor cells (NPCs) can transform into medulloblastomas (MBs), the most common malignant brain tumor in children. As a result, the GC system may play a critical role in MB development. Up to 30% of human medulloblastomas are thought to be driven by excessive Hedgehog signaling (a potent EGL mitogen). Consistent with this idea, mice with mutations causing constitutive Hedgehog signaling are also vulnerable to MB formation. Interestingly, excessive Hedgehog signaling is also thought to decrease GC stimulation in the EGL due to selective GC metabolism. Therefore, we used MB prone (Patched) mice to examine if this vulnerability still exists during preneoplastic tumor transformation. We found GC stimulation potently increased apoptotic cell death in preneoplasms. This suggests GCs may both play a role in MB development and have potential as a therapeutic treatment.