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Vol. 20, Issue 7, 2015-2029, April 1, 2009

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USP9X Enhances the Polarity and Self-Renewal of Embryonic Stem Cell-derived Neural Progenitors

Lachlan A. Jolly^*,,, Verdon Taylor, and Stephen A. Wood^*,,||

*Child Health Research Institute, North Adelaide, South Australia 5006, Australia; School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia; SA Pathology, Womens and Childrens Hospital, Adelaide, South Australia 5006, Australia; and Department of Molecular Embryology, Max-Planck Institute of Immunobiology, D-79108 Freiburg, Germany

Submitted June 12, 2008; Revised November 7, 2008; Accepted January 22, 2009
Monitoring Editor: Marianne Bronner-Fraser

The substrate-specific deubiquitylating enzyme USP9X is a putative "stemness" gene expressed in many progenitor cell populations. To test its function in embryonic stem cell-derived neural progenitor/stem cells, we expressed USP9X from a Nestin promoter. Elevated USP9X levels resulted in two phenomena. First, it produced a dramatically altered cellular architecture wherein the majority (>80%) of neural progenitors was arranged into radial clusters. These progenitors expressed markers of radial glial cells and were highly polarized with adherens junction proteins (N-cadherin, β-catenin, and AF-6) and apical markers (Prominin1, atypical protein kinase C-) as well as Notch, Numb, and USP9X itself, concentrated at the center. The cluster centers were also devoid of nuclei and so resembled the apical end-feet of radial progenitors in the neural tube. Second, USP9X overexpression caused a fivefold increase in the number of radial progenitors and neurons, in the absence of exogenous growth factors. 5-Bromo-2'-deoxyuridine labeling, as well as the examination of the brain lipid-binding protein:βIII-tubulin ratio, indicated that nestin-USP9X enhanced the self-renewal of radial progenitors but did not block their subsequent differentiation to neurons and astrocytes. nestin-USP9X radial progenitors reformed clusters after passage as single cells, whereas control cells did not, suggesting it aids the establishment of polarity. We propose that USP9X-induced polarization of these neural progenitors results in their radial arrangement, which provides an environment conducive for self-renewal.

^|| Present address: National Centre for Adult Stem Cell Research, Eskitis Institute for Cellular and Molecular Therapies, Griffith University, Nathan, QLD, 4111, Australia.

Address correspondence to: Stephen A. Wood (s.wood{at}griffith.edu.au)

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