Negative Regulation of Neural Stem/Progenitor Cell Proliferation by the
            <i>Pten</i>
            Tumor Suppressor Gene in Vivo

Groszer, Matthias; Erickson, Rebecca J.; Scripture-Adams, Deirdre D.; Lesche, Ralf; Trumpp, Andreas; Zack, Jerome A.; Kornblum, Harley I.; Liu, Xin; Wu, Hong

doi:10.1126/science.1065518

Cited by 741 publications

(682 citation statements)

References 23 publications

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“…We confirmed successful targeting of Pten in the intestine by PCR analysis (Fig. 1f), which showed deletion of Pten exon 5 encoding the phosphatase motif 22 .…”

Section: Induced Inactivation Of Pten Leads To Intestinal Polyposissupporting

confidence: 63%

“…To determine the time course of PTEN loss, we generated Mx1-Cre:Pten fl/fl mice 22 carrying a Z/EG reporter, so that Cre-mediated Pten deletion would be reported by the expression of green fluorescent protein (GFP). We induced gene deletion at or before weaning with polyinosinic-polycytidylic acid (pIpC), which provokes innate immune and inflammatory responses and generates interferon that, in turn, activates Cre expression 23 .…”

Section: Induced Inactivation Of Pten Leads To Intestinal Polyposismentioning

confidence: 99%

“…In our mutants 22 , loss of PTEN function is expected to result in activation of Akt (as measured by the phosphorylated form of Akt-Thr473 (hereafter 'p-Akt') and phosphorylation of the Akt downstream target GSK3β at Ser9 ('p-GSK3β') 16 . Indeed, protein blot analysis demonstrated increased levels of p-Akt and p-GSK3β in the PTENdeficient mice (Fig.…”

Section: Pten Controls Cell Cycle In Intestinal Cryptsmentioning

confidence: 99%

“…In this study, we used the PTEN conditional inactivation mouse model 22 to define the role of the PTEN-Akt pathway in the intestine. We implicate PTEN-deficient stem cells in the origin of polyposis and establish a molecular mechanism by which the PTEN-Akt and Wnt-β-catenin pathways coordinate to regulate intestinal homeostasis.…”

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PTEN-deficient intestinal stem cells initiate intestinal polyposis

et al. 2007

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Intestinal polyposis, a precancerous neoplasia, results primarily from an abnormal increase in the number of crypts, which contain intestinal stem cells (ISCs). In mice, widespread deletion of the tumor suppressor Phosphatase and tensin homolog (PTEN) generates hamartomatous intestinal polyps with epithelial and stromal involvement. Using this model, we have established the relationship between stem cells and polyp and tumor formation. PTEN helps govern the proliferation rate and number of ISCs and loss of PTEN results in an excess of ISCs. In PTENdeficient mice, excess ISCs initiate de novo crypt formation and crypt fission, recapitulating crypt production in fetal and neonatal intestine. The PTEN-Akt pathway probably governs stem cell activation by helping control nuclear localization of the Wnt pathway effector β-catenin. Akt phosphorylates β-catenin at Ser552, resulting in a nuclear-localized form in ISCs. Our observations show that intestinal polyposis is initiated by PTEN-deficient ISCs that undergo excessive proliferation driven by Akt activation and nuclear localization of β-catenin. Accession codes. Gene Expression Omnibus (GEO): GSE6078.URLs. GEO: http://www.ncbi.nlm.nih.gov/projects/geo/.Supplementary information is available on the Nature Genetics website. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. HHS Public AccessAuthor manuscript Nat Genet. Author manuscript; available in PMC 2015 December 16. Published in final edited form as:Nat Genet. 2007 February ; 39(2): 189-198. doi:10.1038/ng1928. Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptThe failure of most current therapies to cure cancer has led to the hypothesis that treatments targeted at malignant proliferation spare a more slowly cycling 'cancer stem cell' population that has the ability to regenerate the tumor 1 . Recently, cancer stem cells have been identified and shown to seed tumors upon transplantation into a secondary host [2][3][4] . However, little is known about the process by which mutation(s) in a stem cell result in primary tumor initiation.Although there are many 'causes' of intestinal cancer, it is well established that almost all cases begin with the development of benign polyps, mainly involving benign neoplastic proliferation of epithelium. The epithelium of the small intestine is composed of a proliferation compartment (crypt) and a differentiation compartment in the villus (Fig. 1a). ISCs, located near the crypt base and above Paneth cells 5,6 , give rise to enterocytes, goblet cells, enteroendocrine cells and Paneth cells [6][7][8] . Intestinal polyposis features a substantial increase in the number of crypts (crypt expansion) and a reduction in epithelial cell differentiation 6,7,9,10 . A key question 7,9,11 is whether stem cells are involved in the abnormal crypt expansion during polyp initiation.Studies of human hereditary intestinal polyposis syndromes (which typically, but not uniformly, predispose affected individuals to gastrointes...

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“…We confirmed successful targeting of Pten in the intestine by PCR analysis (Fig. 1f), which showed deletion of Pten exon 5 encoding the phosphatase motif 22 .…”

Section: Induced Inactivation Of Pten Leads To Intestinal Polyposissupporting

confidence: 63%

Section: Induced Inactivation Of Pten Leads To Intestinal Polyposismentioning

confidence: 99%

Section: Pten Controls Cell Cycle In Intestinal Cryptsmentioning

confidence: 99%

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PTEN-deficient intestinal stem cells initiate intestinal polyposis

et al. 2007

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“…The tumor suppressor phosphatase and tensin homolog (PTEN) plays a critical role in neural precursor proliferation and growth [26]. It regulates the G1-S transition by modulating the expression of cyclin D1 and p27 kip1 [27], and it negatively regulates the proliferation of embryonic [28,29] and postnatal neural stem cells [30]. To investigate whether GABA A R activation could promote the cell cycle entry in precursors, sorted EGFR high and EGFR low cells were plated on chamber slides and treated for 6 hours with muscimol (25 lM) or bicuculline (50 lM) and then processed for immunocytochemistry to analyze PTEN and cyclin D1 expression.…”

Section: Gaba a Rs Activation Promotes The Cell Cycle Entry In Neonatmentioning

confidence: 99%

GABAA Receptor Signaling Induces Osmotic Swelling and Cell Cycle Activation of Neonatal Prominin+ Precursors

et al. 2011

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Signal-regulated changes in cell size affect cell division and survival and therefore are central to tissue morphogenesis and homeostasis. In this respect, GABA receptors (GABA A Rs) are of particular interest because allowing anions flow across the cell membrane modulates the osmolyte flux and the cell volume. Therefore, we have here investigated the hypothesis that GABA may regulate neural stem cell proliferation by inducing cell size changes. We found that, besides neuroblasts, also neural precursors in the neonatal murine subependymal zone sense GABA via GABA A Rs. However, unlike in neuroblasts, where it induced depolarization-mediated [Ca 21 ] i increase, GABA A Rs activation in precursors caused hyperpolarization. This resulted in osmotic swelling and increased surface expression of epidermal growth factor receptors (EGFRs). Furthermore, activation of GABA A Rs signaling in vitro in the presence of EGF modified the expression of the cell cycle regulators, phosphatase and tensin homolog and cyclin D1, increasing the pool of cycling precursors without modifying cell cycle length. A similar effect was observed on treatment with diazepam. We also demonstrate that GABA and diazepam responsive precursors represent prominin 1 stem cells. Finally, we show that as in in vitro also in in vivo a short administration of diazepam promotes EGFR expression in prominin 1 stem cells causing activation and cell cycle entry. Thus, our data indicate that endogenous GABA is a part of a regulatory mechanism of size and cell cycle entry of neonatal stem cells. Our results also have potential implications for the therapeutic practices that involve exposure to GABA A Rs modulators during neurodevelopment. STEM CELLS 2011;29:307-319 Disclosure of potential conflicts of interest is found at the end of this article.

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