Tamoxifen-inducible glia-specific Cre mice for somatic mutagenesis in oligodendrocytes and Schwann cells

Inducible transgenesis provides a valuable technique for the analysis of gene function in vivo. We report the generation and characterization of mouse lines carrying glia lineage-specific transgenes expressing an improved variant of the tamoxifen-inducible Cre recombinase, CreERT2, where the recombinase is fused to a mutated ligand binding domain of the human estrogen receptor. Using a PLP-CreERT2 transgene, we have generated mice that show specific inducible Cre function, as analyzed by cross-breeding experiments into the Rosa26 Cre-LacZ reporter line, in developing and adult Schwann cells, in mature myelinating oligodendrocytes, and in undifferentiated NG2-positive oligodendrocyte precursors in the adult. Using a P0Cx-CreERT2 transgene, we have also established mouse lines with inducible Cre function specifically in the Schwann cell lineage. These tamoxifen-inducible CreERT2 lines will allow detailed spatiotemporally controlled analysis of gene functions in loxP-based conditional mutant mice in both developing and adult Schwann cells and in the oligodendrocyte lineage.

[1]  M. Lewandoski Conditional control of gene expression in the mouse , 2001, Nature Reviews Genetics.

[2]  L. Wrabetz,et al.  Hypomyelinating peripheral neuropathies and schwannomas in transgenic mice expressing SV40 T-antigen , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[3]  P Chambon,et al.  Temporally-controlled site-specific mutagenesis in the basal layer of the epidermis: comparison of the recombinase activity of the tamoxifen-inducible Cre-ER(T) and Cre-ER(T2) recombinases. , 1999, Nucleic acids research.

[4]  W. Colledge Manipulating the mouse embryo (2nd edn) , 1995 .

[5]  E. Casanova,et al.  Inducible site-specific recombination in the brain. , 1999, Journal of molecular biology.

[6]  N. Baumann,et al.  Biology of oligodendrocyte and myelin in the mammalian central nervous system. , 2001, Physiological reviews.

[7]  Jos Jonkers,et al.  A highly efficient ligand‐regulated Cre recombinase mouse line shows that LoxP recombination is position dependent , 2001, EMBO reports.

[8]  Andras Nagy,et al.  Cre recombinase: The universal reagent for genome tailoring , 2000, Genesis.

[9]  A. McMahon,et al.  Modification of gene activity in mouse embryos in utero by a tamoxifen-inducible form of Cre recombinase , 1998, Current Biology.

[10]  U. Suter,et al.  The Early Life of a Schwann Cell , 2002, Biological chemistry.

[11]  R Kuhn,et al.  Temporally and spatially regulated somatic mutagenesis in mice. , 1998, Nucleic acids research.

[12]  P. Chambon,et al.  An efficient system for conditional gene expression in embryonic stem cells and in their in vitro and in vivo differentiated derivatives , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[13]  P Chambon,et al.  Regulation of Cre recombinase activity by mutated estrogen receptor ligand-binding domains. , 1997, Biochemical and biophysical research communications.

[14]  Hideo Fujiwara,et al.  Hyperphosphorylation and insolubility of α‐synuclein in transgenic mouse oligodendrocytes , 2002 .

[15]  D. Maxwell,et al.  An electron microscopic study of the neuroglia during postnatal development of the rat cerebrum , 1968, The Journal of comparative neurology.

[16]  E. Fuchs,et al.  The magical touch: genome targeting in epidermal stem cells induced by tamoxifen application to mouse skin. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[17]  P Chambon,et al.  Ligand-activated site-specific recombination in mice. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[18]  D. Foran,et al.  Myelin acquisition in the central nervous system of the mouse revealed by an MBP-Lac Z transgene , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[19]  E. Ziff,et al.  Transcription factors in melanocyte development: distinct roles for Pax-3 and Mitf , 2001, Mechanisms of Development.

[20]  R. Mirsky,et al.  Schwann cells and their precursors emerge as major regulators of nerve development , 1999, Trends in Neurosciences.

[21]  G. Kidd,et al.  Proteolipid Promoter Activity Distinguishes Two Populations of NG2-Positive Cells throughout Neonatal Cortical Development , 2002, The Journal of Neuroscience.

[22]  U. Suter,et al.  Mouse Genetics in Cell Biology , 2000, Experimental physiology.

[23]  P Chambon,et al.  Site- and time-specific gene targeting in the mouse. , 2001, Methods.

[24]  P. Chambon,et al.  Selective ablation of retinoid X receptor α in hepatocytes impairs their lifespan and regenerative capacity , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[25]  A. Campagnoni,et al.  Regional expression of myelin protein genes in the developing mouse brain: In situ hybridization studies , 1988, Journal of neuroscience research.

[26]  B. Popko,et al.  Inducible site‐specific recombination in myelinating cells , 2003, Genesis.

[27]  Andrew P McMahon,et al.  Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse. , 2002, Developmental biology.

[28]  R. Skoff,et al.  Pattern of myelination and distribution of neuroglial cells along the developing optic system of the rat and rabbit , 1980, The Journal of comparative neurology.

[29]  S. Fawell,et al.  Identification of residues in the estrogen receptor that confer differential sensitivity to estrogen and hydroxytamoxifen. , 1993, Molecular endocrinology.

[30]  I. Jackson,et al.  Activation of the receptor tyrosine kinase Kit is required for the proliferation of melanoblasts in the mouse embryo. , 1997, Developmental biology.

[31]  K. Fischbeck,et al.  Studies in transgenic mice indicate a loss of connexin32 function in X-linked Charcot-Marie-Tooth disease. , 1999, Journal of neuropathology and experimental neurology.

[32]  G. Evan,et al.  A modified oestrogen receptor ligand-binding domain as an improved switch for the regulation of heterologous proteins. , 1995, Nucleic acids research.

[33]  Impaired adipogenesis and lipolysis in the mouse upon selective ablation of the retinoid X receptor alpha mediated by a tamoxifen-inducible chimeric Cre recombinase (Cre-ERT2) in adipocytes. , 2001 .

[34]  B. Fuss,et al.  Normal CNS Myelination in Transgenic Mice Overexpressing MHC Class I H-2Ld in Oligodendrocytes , 2001, Molecular and Cellular Neuroscience.

[35]  C. Readhead,et al.  A myelin proteolipid protein-LacZ fusion protein is developmentally regulated and targeted to the myelin membrane in transgenic mice , 1993, The Journal of cell biology.

[36]  J. Vonesch,et al.  Spatio-temporally controlled site-specific somatic mutagenesis in the mouse. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[37]  P. Wight,et al.  The first intron of the myelin proteolipid protein gene confers cell type-specific expression by a transcriptional repression mechanism in non-expressing cell types. , 1997, Gene.

[38]  Philippe Soriano Generalized lacZ expression with the ROSA26 Cre reporter strain , 1999, Nature Genetics.

[39]  P. Chambon,et al.  Temporally controlled targeted somatic mutagenesis in the mouse brain , 2001, The European journal of neuroscience.

[40]  P. Chambon,et al.  Conditional site-specific recombination in mammalian cells using a ligand-dependent chimeric Cre recombinase. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[41]  R. Palmiter,et al.  P0 promoter directs expression of reporter and toxin genes to schwann cells of transgenic mice , 1992, Neuron.