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The Journal of Neuroscience, November 16, 2005, 25(46):10773-10785; doi:10.1523/JNEUROSCI.3207-05.2005

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Cellular/Molecular
PBK/TOPK, a Proliferating Neural Progenitor-Specific Mitogen-Activated Protein Kinase Kinase

J. D. Dougherty,^1,2,3 A. D. R. Garcia,⁵ I. Nakano,^3,4,6 M. Livingstone,⁷ B. Norris,⁷ R. Polakiewicz,⁷ E. M. Wexler,^2,6 M. V. Sofroniew,⁵ H. I. Kornblum,^3,4,6 and D. H. Geschwind^1,2,3,6

¹Interdepartmental Program in the Neurosciences, ²Program in Neurogenetics, Neurology Department, ³Neural Stem Cell Research Center, ⁴Departments of Molecular and Medical Pharmacology and Pediatrics, ⁵Department of Neurobiology and Brain Research Institute, and ⁶Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095-1769, and ⁷Cell Signaling Technology, Beverly, Massachusetts, 01915

We performed genomic subtraction coupled to microarray-based gene expression profiling and identified the PDZ (postsynaptic density-95/Discs large/zona occludens-1)-binding kinase/T-LAK (lymphokine-activated killer T cell) cell originating protein kinase (PBK/TOPK) as a gene highly enriched in neural stem cell cultures. Previous studies have identified PBK/TOPK as a mitogen-activated protein kinase (MAPK) kinase that phosphorylated P38 MAPK but with no known expression or function in the nervous system. First, using a novel, bioinformatics-based approach to assess cross-correlation in large microarray datasets, we generated the hypothesis of a cell-cycle-related role for PBK/TOPK in neural cells. We then demonstrated that both PBK/TOPK and P38 are activated in a cell-cycle-dependant manner in neuronal progenitor cells in vitro, and inhibition of this pathway disrupts progenitor proliferation and self-renewal, a core feature of progenitors. In vivo, PBK/TOPK is expressed in rapidly proliferating cells in the adult subependymal zone (SEZ) and early postnatal cerebellar external granular layer. Using an approach based on transgenically targeted ablation and lineage tracing in mice, we show that PBK/TOPK-positive cells in the SEZ are GFAP negative but arise from GFAP-positive neural stem cells during adult neurogenesis. Furthermore, ablation of the adult stem cell population leads to concomitant loss of PBK/TOPK-positive cells in the SEZ. Together, these studies demonstrate that PBK/TOPK is a marker for transiently amplifying neural progenitors in the SEZ. Additionally, they suggest that PBK/TOPK plays an important role in these progenitors, and further implicates the P38 MAPK pathway in general, as an important regulator of progenitor proliferation and self-renewal.

Key words: subventricular zone; microarray; neural stem cell; progenitor cell; P38 MAPK; external granular layer; rostral migratory stream

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Received May 19, 2005; revised September 29, 2005; accepted October 3, 2005.

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