An allelic series for the leptin receptor gene generated by CRE and FLP recombinase

Julie E. McMinn, Shun Mei Liu, Ioannis Dragatsis, Paula Dietrich, Thomas Ludwig, Sandra Eiden, Streamson C. Chua

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

Body weight regulation is mediated through several major signaling pathways, some of which have been delineated by positional cloning of spontaneous genetic mutations in mice. Leprdb/db mice are obese due to a defect in the signaling portion of the leptin receptor, which has led to extensive study of this highly conserved system over the past several years. We have created an allelic series at Lepr for the further examination of LEPR signaling phenotypes using both the FLP/frt and CRE/foxP systems. By inserting a frt-PGK-neo-frt sequence in Lepr intron 16, we have generated a conditional gene repair Lepr allele (Lepr-neo) that elicits morbid obesity, diabetes, and infertility in homozygous mice, recapitulating the obesity syndrome of Lep db/db mice. Thus, in vivo excision of the PGK-neo cassette with a FLP recombinase transgene restores the lean and fertile phenotype to Lepr flox/flox mice. In the same construct, we have also inserted loxP sites that flank Lepr coding exon 17, a region that encodes a JAK docking site required for STAT3 signaling. CRE-mediated excision of Lepr coding exon 17 from Lepr with a frameshift in subsequent exons results in a syndrome of obesity, diabetes, and infertility in LeprΔ17/Δ17 mice, which is indistinguishable from Leprneo/neo and Leprdb/db mice. We conclude that suppression of Lepr gene expression by PGK-neo is phenotypically equivalent to deletion of the Lepr signaling motifs, and therefore the Lepr neo/neo mouse may be used to investigate conditional gene repair of Lepr signaling deficiency.

Original languageEnglish (US)
Pages (from-to)677-685
Number of pages9
JournalMammalian Genome
Volume15
Issue number9
DOIs
StatePublished - Sep 2004
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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    McMinn, J. E., Liu, S. M., Dragatsis, I., Dietrich, P., Ludwig, T., Eiden, S., & Chua, S. C. (2004). An allelic series for the leptin receptor gene generated by CRE and FLP recombinase. Mammalian Genome, 15(9), 677-685. https://doi.org/10.1007/s00335-004-2340-1