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The Journal of Neuroscience, September 13, 2006, 26(37):9593-9602; doi:10.1523/JNEUROSCI.2815-06.2006

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Development/Plasticity/Repair
High Levels of Cre Expression in Neuronal Progenitors Cause Defects in Brain Development Leading to Microencephaly and Hydrocephaly

Paolo E. Forni,^1,4,5 Claudio Scuoppo,^1,4 Itaru Imayoshi,⁶ Riccardo Taulli,^1,4 Walter Dastrù,^2,3 Valentina Sala,^1,4 Ulrich A. K. Betz,⁷ Patrizia Muzzi,¹ Daniela Martinuzzi,¹ Alessandro E. Vercelli,¹ Ryoichiro Kageyama,⁶ and Carola Ponzetto^1,4,5

¹Department of Anatomy, Pharmacology, and Forensic Medicine, ²Department of Inorganic, Physical, and Materials Chemistry, ³Center of Molecular Imaging, ⁴Center for Experimental Research and Medical Studies, ⁵Rita Levi-Montalcini Center for Brain Repair, University of Turin, 10126 Turin, Italy, ⁶Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan, and ⁷Merck KGaA, Global Preclinical Research and Development, D-64293 Darmstadt, Germany

Correspondence should be addressed to Paolo Forni, Department of Anatomy, Pharmacology, and Forensic Medicine, University of Turin, Corso Massimo D’Azeglio 52, 10126 Turin, Italy. Email: paolo.forni{at}unito.it

Hydrocephalus is a common and variegated pathology often emerging in newborn children after genotoxic insults during pregnancy (Hicks and D’Amato, 1980). Cre recombinase is known to have possible toxic effects that can compromise normal cell cycle and survival. Here we show, by using three independent nestin Cre transgenic lines, that high levels of Cre recombinase expression into the nucleus of neuronal progenitors can compromise normal brain development. The transgenics analyzed are the nestin Cre Balancer (Bal1) line, expressing the Cre recombinase with a nuclear localization signal, and two nestin CreER^T2 (Cre recombinase fused with a truncated estrogen receptor) mice lines with different levels of expression of a hybrid CreER^T2 recombinase that translocates into the nucleus after tamoxifen treatment. All homozygous Bal1 nestin Cre embryos displayed reduced neuronal proliferation, increased aneuploidy and cell death, as well as defects in ependymal lining and lamination of the cortex, leading to microencephaly and to a form of communicating hydrocephalus. An essentially overlapping phenotype was observed in the two nestin CreER^T2 transgenic lines after tamoxifen mediated-CreER^T2 translocation into the nucleus. Neither tamoxifen-treated wild-type nor nestin CreER^T2 oil-treated control mice displayed these defects. These results indicate that some forms of hydrocephalus may derive from a defect in neuronal precursors proliferation. Furthermore, they underscore the potential risks for developmental studies of high levels of nuclear Cre in neurogenic cells.

Key words: Cre recombinase; nestin Cre; Cre genotoxicity; hydrocephalus; cortex; neuronal progenitor cell

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Received May 27, 2005; revised Aug. 3, 2005; accepted Aug. 3, 2006.

Correspondence should be addressed to Paolo Forni, Department of Anatomy, Pharmacology, and Forensic Medicine, University of Turin, Corso Massimo D’Azeglio 52, 10126 Turin, Italy. Email: paolo.forni{at}unito.it

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