Article ; Online: Differential CRE Expression in Lhrh-cre and GnRH-cre Alleles and the Impact on Fertility in Otx2-Flox Mice.
2019 Volume 108, Issue 4, Page(s) 328–342
Abstract: There is an increasing trend in studies utilizing cell-specific deletion of genes through conditional gene deletion by CRE recombination. Despite numerous advantages, this strategy also has limitations such as ectopic CRE-expression and germline ... ...
| Abstract | There is an increasing trend in studies utilizing cell-specific deletion of genes through conditional gene deletion by CRE recombination. Despite numerous advantages, this strategy also has limitations such as ectopic CRE-expression and germline recombination. Two commonly used gonadotropin-releasing hormone (Gnrh)-driven CRE-expressing mice both target GnRH neurons. However, a direct comparison of the cells targeted and their phenotypic outcome have not yet been presented. To compare where recombination takes place, we crossed the Gnrh-cre and Lhrh-cre lines with the Rosa26-LacZ reporter mouse. Lhrh-cre allowed recombination of the Rosa26-LacZ gene in ∼700 cells, which is comparable to the GnRH neuronal population. Surprisingly, there were > 20 times more LacZ expressing cells in the adult Gnrh-cre:Rosa26-LacZ than the Lhrh-cre:Rosa26-LacZ brain. The greatest differences in targeting of the Gnrh-cre and Lhrh-cre lines were found in the septum, the suprachiasmatic nucleus, and the septohypothalamic area. This difference in cells targeted was present from embryonic day 12. A prior study using the Gnrh-cre to delete the transcription factor Otx2 found fewer GnRH neurons, leading to male and female subfertility. To recapitulate this study, we performed a fertility assay in Otx2:Lhrh-cre mice. We confirmed the requirement for Otx2 in GnRH neuron development, fertility and correct gonadotropin hormone release in Otx2:Lhrh-cre males, but the subfertility was more modest than in Otx2:Gnrh-cre and absent in female Otx2:Lhrh-cre. This suggests that ectopic expression of Gnrh-cre contributes to the reproductive phenotype observed. Finally, the Cre alleles caused germline recombination of the flox allele when transmitted from either parent, generating embryonic lethal knock-out offspring, producing smaller live litters. |
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| MeSH term(s) | Alleles ; Animals ; Brain/metabolism ; Gonadotropin-Releasing Hormone/genetics ; Gonadotropin-Releasing Hormone/metabolism ; Infertility/genetics ; Mice, Transgenic ; Neurons/metabolism ; Otx Transcription Factors/genetics ; Promoter Regions, Genetic/genetics ; RNA, Messenger/metabolism |
| Chemical Substances | Otx Transcription Factors ; Otx2 protein, mouse ; RNA, Messenger ; Gonadotropin-Releasing Hormone (33515-09-2) |
| Language | English |
| Publishing date | 2019-02-10 |
| Publishing country | Switzerland |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 123303-8 |
| ISSN | 1423-0194 ; 0028-3835 |
| ISSN (online) | 1423-0194 |
| ISSN | 0028-3835 |
| DOI | 10.1159/000497791 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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