Targeted inactivation of dipeptidyl peptidase 9 enzymatic activity causes mouse neonate lethality.
Dipeptidyl Peptidase (DPP) 4 and related dipeptidyl peptidases are emerging as current and potential therapeutic targets. DPP9 is an intracellular protease that is regulated by redox status and by SUMO1. DPP9 can influence antigen processing, epidermal growth factor (EGF)-mediated signaling and tumor biology. We made the first gene knock-in (gki) mouse with a serine to alanine point mutation at the DPP9 active site (S729A). Weaned heterozygote DPP9 (wt/S729A) pups from 110 intercrosses were indistinguishable from wild-type littermates. No homozygote DPP9 (S729A/S729A) weaned mice were detected. DPP9 (S729A/S729A) homozygote embryos, which were morphologically indistinguishable from their wild-type littermate embryos at embryonic day (ED) 12.5 to ED 17.5, were born live but these neonates died within 8 to 24 hours of birth. All neonates suckled and contained milk spots and were of similar body weight. No gender differences were seen. No histological or DPP9 immunostaining pattern differences were seen between genotypes in embryos and neonates. Mouse embryonic fibroblasts (MEFs) from DPP9 (S729A/S729A) ED13.5 embryos and neonate DPP9 (S729A/S729A) mouse livers collected within 6 hours after birth had levels of DPP9 protein and DPP9-related proteases that were similar to wild-type but had less DPP9/DPP8-derived activity. These data confirmed the absence of DPP9 enzymatic activity due to the presence of the serine to alanine mutation and no compensation from related proteases. These novel findings suggest that DPP9 enzymatic activity is essential for early neonatal survival in mice.
Centenary Institute, Camperdown and Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
Margaret G
MG
Gall
Yiqian
Y
Chen
Ana Julia
AJ
Vieira de Ribeiro
Hui
H
Zhang
Charles G
CG
Bailey
Derek S
DS
Spielman
Denise M T
DM
Yu
Mark D
MD
Gorrell
D019943:Amino Acid Substitution; D000818:Animals; D000831:Animals, Newborn / Q000002:abnormalities* / Q000235:genetics / Q000378:metabolism; D003433:Crosses, Genetic; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000172:deficiency / Q000235:genetics*; D004622:Embryo, Mammalian; D057075:Enzyme Assays; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D018703:Founder Effect; D015870:Gene Expression; D055879:Gene Knock-In Techniques; D006579:Heterozygote; D006720:Homozygote; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic / Q000002:abnormalities / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation
D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C585326:dipeptidyl peptidase 9, mouse