Disruption of cerebellar granular neuronal precursor (GNP) maturation can result in defects in motor coordination and learning, or in medulloblastoma, the most common childhood brain tumor. The Sonic Hedgehog (Shh) pathway is important for GNP proliferation; however, the factors regulating the extent and timing of GNP proliferation, as well as GNP differentiation and migration are poorly understood. The p53 tumor suppressor has been shown to negatively regulate the activity of the Shh effector, Gli1, in neural stem cells; however, the contribution of p53 to the regulation of Shh signaling in GNPs during cerebellar development has not been determined. Here, we exploited a hypomorphic allele of Mdm2 (Mdm2puro), which encodes a critical negative regulator of p53, to alter the level of wild-type MDM2 and p53 in vivo. We report that mice with reduced levels of MDM2 and increased levels of p53 have small cerebella with shortened folia, reminiscent of deficient Shh signaling. Indeed, Shh signaling in Mdm2-deficient GNPs is attenuated, concomitant with decreased expression of the Shh transducers, Gli1 and Gli2. We also find that Shh stimulation of GNPs promotes MDM2 accumulation and enhances phosphorylation at serine 166, a modification known to increase MDM2-p53 binding. Significantly, loss of MDM2 in Ptch1+/− mice, a model for Shh-mediated human medulloblastoma, impedes cerebellar tumorigenesis. Together, these results place MDM2 at a major nexus between the p53 and Shh signaling pathways in GNPs, with key roles in cerebellar development, GNP survival, cerebellar foliation, and MB tumorigenesis.
Noise-band vocoders are often used to simulate the signal processing algorithms used in cochlear implants (CIs), producing acoustic stimuli that may be presented to normal hearing (NH) subjects. Such evaluations may obviate the heterogeneity of CI user populations, achieving greater experimental control than when testing on CI subjects. However, it remains an open question whether advancements in algorithms developed on NH subjects using a simulator will necessarily improve performance in CI users. This study assessed the similarity in vowel identification of CI subjects and NH subjects using an 8-channel noise-band vocoder simulator configured to match input and output frequencies or to mimic output after a basalward shift of input frequencies. Under each stimulus condition, NH subjects performed the task both with and without feedback/training. Similarity of NH subjects to CI users was evaluated using correct identification rates and information theoretic approaches. Feedback/training produced higher rates of correct identification, as expected, but also resulted in error patterns that were closer to those of the CI users. Further evaluation remains necessary to determine how patterns of confusion at the token level are affected by the various parameters in CI simulators, providing insight into how a true CI simulation may be developed to facilitate more rapid prototyping and testing of novel CI signal processing and electrical stimulation strategies.
During post-natal cerebellar development, Granule Neuron Precursors (GNPs) undergo a proliferative expansion in response to Sonic hedgehog (Shh) signaling, prior to differentiation and migration to their final niche. Aberrations in this tightly controlled process can tip the balance toward persistent proliferation leading to Medulloblastoma (MB), or toward apoptosis or premature differentiation leading to neurodegeneratiion. Here, we report that MDM2, the principal inhibitor of the p53 tumor suppressor protein, is required for cerebellum development as well as for MB tumorigenesis. Our studies employed a novel hypomorphic allele of Mdm2 (Mdm2puro) in combination with the Mdm2del7-9 null allele. Mdm2puro/del7-9 mice express ∼30% of the wild-type level of MDM2. Mdm2puro/del7-9 cerebella exhibit decreased foliation, reduction in GNP numbers, and laminar disorganization. These phenotypes are attributed, in part, to high levels of p53-dependent apoptosis. In addition, we have recently determined through fate mapping studies that loss of MDM2 also promotes the premature migration of GNPs. Global transcriptome analyses of the Mdm2puro/del7-9 cerebellum supports dysregulation of the transcriptional programs that regulate GNP differentiation. Further, Western blot analyses reveal an increase in the pro-differentiation protein, Numb, and the neuronal maturation marker, βIII-Tubulin, in GNPs. A concomitant decrease in Gli1 and Gli2, two effectors of Shh signaling known to be degraded by Numb, suggests an increase in Numb activity. These experiments suggest that loss of MDM2 and subsequent increase in p53 activity accelerates GNPs migration and possibly favors GNP differentiation over proliferation. In complementary experiments, we employed Shh-responsive primary GNP cultures from wild-type mice. Shh stimulation of GNPs results in an increase in the steady state level of MDM2 and an increase in MDM2 phosphorylation at Ser166, a modification known to enhance the anti-p53 function of MDM2. These findings suggest that Shh signaling may upregulate MDM2 to prevent p53 activation during GNP proliferation. In keeping with the concept that GNP proliferation and MB tumor formation are governed by similar mechanisms, we also observed increased levels of p-MDM2Ser166 in Shh-induced preneoplastic lesions (PNLs) and MB tumors in a Ptch1+/- mice, a model of human MB. Notably, a 70% reduction in the level of MDM2 in these mice abrogates the formation of PNLs, supporting a key role for MDM2 in the initiation of some types of MB. Overall, our results suggest that MDM2 mediated inhibition of p53 plays in important role in survival and migration of GNPs cerebellum development. This role of MDM2 may be high-jacked by deregulated Shh signaling in certain MB tumors thereby limiting the tumor suppressive function of p53 and obviating a need for p53 gene mutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5213. doi:1538-7445.AM2012-5213
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