Knock-in of diphteria toxin A chain gene at Ins2 locus: effects on islet development and localization of Ins2 expression in the brain

Author： Lamotte Luciane  

Publisher： Springer Publishing Company

ISSN： 0962-8819

Source： Transgenic Research, Vol.13, Iss.5, 2004-10, pp. : 463-473

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Abstract

We report here knock-in of diphteria toxin A chain (dta) gene at the Ins2 locus, using the strategy previously employed to insert lacZ under control of the Ins2 promoter. Mutant Ins2dta/+, Ins2dta/lacZ or Ins2lacZ/+ mouse pups were generated by breeding and analyzed to study the effects of toxigenetic -cell ablation on islet development and to localize the extrapancreatic Ins2 expression site in the brain. Ins2dta/+ and Ins2dta/lacZ pups developed a severe diabetic ketoacidosis and died rapidly. Histological analysis of their pancreas revealed that -cells completely disappeared in their islets as evidenced by loss of lacZ activity or insulin immunonostaining. -cell ablation did not alter the size of other islet cell populations which were normal at birth, although the glucagon-cell population was reduced by 85% at embryonic day E12.5. In the brain, comparative analysis of lacZ expression in Ins2lacZ/+ and Ins2dta/lacZ mice identified the choroid plexus (CP) as a major Ins2 expression site. This finding was confirmed by RT-PCR analysis of insulin transcripts in RNAs prepared from microdissected wild-type CP. Transcripts for other key -cell markers, with the notable exception of Pdx-1, were also found in CP RNAs. These results must revive interest in studies focused on extrapancreatic insulin gene expression.

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