High levels of Cre expression in neuronal progenitors cause defects in brain development leading to microencephaly and hydrocephaly.
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.
Forni
Paolo E
PE
Department of Anatomy, Pharmacology, and Forensic Medicine, University of Turin, 10126 Turin, Italy. paolo.forni@unito.it
Scuoppo
Claudio
C
Imayoshi
Itaru
I
Taulli
Riccardo
R
Dastrù
Walter
W
Sala
Valentina
V
Betz
Ulrich A K
UA
Muzzi
Patrizia
P
Martinuzzi
Daniela
D
Vercelli
Alessandro E
AE
Kageyama
Ryoichiro
R
Ponzetto
Carola
C
D000782:Aneuploidy; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000002:abnormalities* / Q000201:enzymology / Q000503:physiopathology; D016923:Cell Death / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D004805:Ependyma / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006849:Hydrocephalus / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D019426:Integrases / Q000235:genetics / Q000378:metabolism*; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008831:Microcephaly / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009421:Nervous System Malformations / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D064231:Nestin; D009474:Neurons / Q000201:enzymology; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D013234:Stem Cells / Q000201:enzymology*; D013629:Tamoxifen / Q000494:pharmacology
D015415:Biomarkers; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D019913:Nuclear Localization Signals; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; C045073:Cre recombinase; D019426:Integrases