Inducible site-specific recombination in myelinating cells

To explore the function of genes expressed by myelinating cells we have developed a model system that allows for the inducible ablation of predetermined genes in oligodendrocytes and Schwann cells. The Cre/loxP recombination system provides the opportunity to generate tissue‐specific somatic mutations in mice. We have used a fusion protein between the Cre recombinase and a mutated ligand‐binding domain of the human estrogen receptor (CreERT) to obtain inducible, site‐specific recombination. CreERT expression was placed under the transcriptional control of the regulatory sequences of the myelin proteolipid protein (PLP) gene, which is abundantly expressed in oligodendrocytes and to a lesser extent in Schwann cells. The CreERT fusion protein translocated to the nucleus and mediated the recombination of a LacZ reporter transgene in myelinating cells of PLP/CreERT mice injected with the synthetic steroid tamoxifen. In untreated animals CreERT remained cytoplasmic, and there was no evidence of recombination. The PLP/ CreERT animals should be very useful in elucidating and distinguishing a particular gene's function in the formation and maintenance of the myelin sheath and in analyzing mature oligodendrocyte function in pathological conditions. genesis 35:63–72, 2003. © 2002 Wiley‐Liss, Inc.