Role Of Postnatal Neurogenesis Research Articles

PM-06 * DIFFERENTIAL SPLICING OF PYRUVATE KINASE REGULATES PROGENITOR CELL CYCLE AND MEDULLOBLASTOMA TUMORIGENESIS

BACKGROUND: We have previously shown that aerobic glycolysis, a hallmark of cancer metabolism, plays a physiological role in postnatal neurogenesis and is co-opted in medulloblastoma. Medulloblastoma, the most common malignant brain tumor in children, arises from cerebellar progenitors that normally proliferate in the first year of life then exit the cell cycle. Processes that regulate the developmental proliferation of neural progenitors may facilitate tumorigenesis when activated aberrantly. We have identified Pyruvate kinase isoform M2 (PKM2) as a developmentally-regulated enzyme that accelerates medulloblastoma tumorigenesis in a mouse model and is a potential target for novel cancer therapies. METHODS: We examined metabolism and proliferation in mice with and without a conditional deletion of PkM2 using NMR-based metabolomics, immunohistochemistry and Western blot. We examined the importance of PkM2 in medulloblastoma tumorigenesis by analyzing the survival of medulloblastoma-prone ND2: SmoA1 mice with and without PkM2 deletion. RESULTS: Brain progenitors specifically splice the PkM gene into the less catalytically active PkM2 isoform, while differentiated neurons uniformly express the constituently active isoform PkM1. Deletion of PkM2 altered energy metabolism, reducing lactic acid production and increasing glutamine consumption. Despite reduced aerobic glycolysis, PkM2-deleted progenitors proliferated more rapidly. In tumor-prone mice, PkM2 deletion accelerated medulloblastoma tumorigenesis and shortened survival. CONCLUSIONS: Our findings of increased tumorigenesis in PkM2-deleted mice demonstrate that PkM2 activity is not required for tumor formation. Further, the generation of lactic acid, per se, does not enhance tumorigenesis. Rather, we propose that PkM2 functions as a less active Pyruvate Kinase isozyme that channels glycolytic intermediates into alternative metabolic fates to support proliferation. Accordingly, splicing PkM into the PkM2 isoform reduces PkM activity in progenitors, and PkM2 deletion enhances this phenotype, accelerating tumor formation in ND2:SmoA1 mice. Strategies that increase PkM2 enzymatic activity may conversely inhibit medulloblastoma growth, providing a novel, metabolic approach to anti-tumor therapy.

The role of postnatal neurogenesis in supporting remote memory and spatial metric processing.

In this study, we determined the contribution of juvenile neurogenesis to the performance of mice on a remote memory for temporally based association task and in a novelty based spatial pattern separation task. This was accomplished by mating homozygous DNMT1-loxP mice with heterozygous GFAP-Cre mice and comparing Cre+ (no postnatal neurogenesis) to Cre- (wild type) littermate offspring. The results indicate that Cre+ mice are impaired relative to Cre- mice in the remote memory for a temporal based association task and in a novelty based spatial pattern separation task. These results support the temporal integration model of Aimone et al., [(2006) Nat Neurosci 9:723-727] and provide further support for an important role for postnatally born neurons in spatial pattern separation. In contrast, Cre+ mice are not impaired relative to Cre- mice in an object-context recognition task and a spatial location recognition task. These latter data suggest that postnatally derived neurons in the dentate gyrus (DG) do not support all spatial and object recognition functions of the DG.

Plexin-B2 Regulates the Proliferation and Migration of Neuroblasts in the Postnatal and Adult Subventricular Zone

In the postnatal forebrain, the subventricular zone (SVZ) contains a pool of undifferentiated cells, which proliferate and migrate along the rostral migratory stream (RMS) to the olfactory bulb and differentiate into granule cells and periglomerular cells. Plexin-B2 is a semaphorin receptor previously known to act on neuronal proliferation in the embryonic brain and neuronal migration in the cerebellum. We show here that, in the postnatal and adult CNS, Plexin-B2 is expressed in the subventricular zone lining the telencephalic ventricles and in the rostral migratory stream. We analyzed Plxnb2(-/-) mice and found that there is a marked reduction in the proliferation of SVZ cells in the mutant. Plexin-B2 expression is downregulated in the olfactory bulb as interneurons initiate radial migration. BrdU labeling and GFP electroporation into postnatal SVZ, in addition to time-lapse videomicroscopy, revealed that neuroblasts deficient for Plexin-B2 migrate faster than control ones and leave the RMS more rapidly. Overall, these results show that Plexin-B2 plays a role in postnatal neurogenesis and in the migration of SVZ-derived neuroblasts.

BM88/Cend1 Expression Levels Are Critical for Proliferation and Differentiation of Subventricular Zone-Derived Neural Precursor Cells

Neural stem cells remain in two areas of the adult mammalian brain, the subventricular zone (SVZ) and the dentate gyrus of the hippocampus. Ongoing neurogenesis via the SVZ-rostral migratory stream pathway maintains neuronal replacement in the olfactory bulb (OB) throughout life. The mechanisms determining how neurogenesis is restricted to only a few regions in the adult, in contrast to its more widespread location during embryogenesis, largely depend on controlling the balance between precursor cell proliferation and differentiation. BM88/Cend1 is a neuronal lineage-specific regulator implicated in cell cycle exit and differentiation of precursor cells in the embryonic neural tube. Here we investigated its role in postnatal neurogenesis. Study of in vivo BM88/Cend1 distribution revealed that it is expressed in low levels in neuronal precursors of the adult SVZ and in high levels in postmitotic OB interneurons. To assess the functional significance of BM88/Cend1 in neuronal lineage progression postnatally, we challenged its expression levels by gain- and loss-of-function approaches using lentiviral gene transfer in SVZ-derived neurospheres. We found that BM88/Cend1 overexpression decreases proliferation and favors neuronal differentiation, whereas its downregulation using new-generation RNA interference vectors yields an opposite phenotype. Our results demonstrate that BM88/Cend1 participates in cell cycle control and neuronal differentiation mechanisms during neonatal SVZ neurogenesis and becomes crucial for the transition from neuroblasts to mature neurons when reaching high levels.