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

Mamm Genome. 2004 Sep;15(9):677-85. doi: 10.1007/s00335-004-2340-1.


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. Lepr(db/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 /loxP 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 Lepr(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 LeprDelta17/Delta17 mice, which is indistinguishable from Lepr(neo/neo) and Lepr(db/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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles*
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Blood Glucose / metabolism
  • Body Temperature Regulation / genetics
  • Body Weight / genetics
  • Body Weight / physiology
  • Chimera
  • Cold Temperature
  • DNA Nucleotidyltransferases / genetics*
  • Disease Models, Animal
  • Eating / genetics
  • Eating / physiology
  • Female
  • Insulin / blood
  • Integrases / genetics*
  • Male
  • Mice
  • Molecular Sequence Data
  • Obesity / genetics*
  • Obesity / metabolism
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Receptors, Cell Surface / biosynthesis
  • Receptors, Cell Surface / genetics*
  • Receptors, Leptin
  • Reverse Transcriptase Polymerase Chain Reaction


  • Blood Glucose
  • Insulin
  • RNA, Messenger
  • Receptors, Cell Surface
  • Receptors, Leptin
  • leptin receptor, mouse
  • Cre recombinase
  • DNA Nucleotidyltransferases
  • FLP recombinase
  • Integrases

Associated data

  • GENBANK/AY589053
  • GENBANK/AY589054
  • GENBANK/AY589055