Targeted inactivation of dipeptidyl peptidase 9 enzymatic activity causes mouse neonate lethality

• Published in: PloS one Vol. 8; no. 11; p. e78378
• Main Authors: Gall, Margaret G, Chen, Yiqian, Vieira de Ribeiro, Ana Julia, Zhang, Hui, Bailey, Charles G, Spielman, Derek S, Yu, Denise M T, Gorrell, Mark D
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06.11.2013; Public Library of Science (PLoS)
• Subjects: Alanine; Amino Acid Substitution; Amino acids; Animals; Animals, Newborn - abnormalities; Animals, Newborn - genetics; Animals, Newborn - metabolism; Antigen processing; Antigens; Apoptosis; B cells; Biology; Birth; Body weight; Cancer; Crosses, Genetic; Deactivation; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - deficiency; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - genetics; Embryo fibroblasts; Embryo, Mammalian; Embryos; Enzymatic activity; Enzyme Assays; Enzymes; Epidermal growth factor; Female; Fibroblasts; Fibroblasts - enzymology; Founder Effect; Gender aspects; Gene Expression; Gene Knock-In Techniques; Gene mutation; Genotypes; Health aspects; Heterozygote; Homeostasis; Homozygote; Inactivation; Infant mortality; Kinases; Lethality; Leukemia; Liver - enzymology; Male; Medical research; Medical schools; Mice; Mice, Transgenic - abnormalities; Mice, Transgenic - genetics; Mice, Transgenic - metabolism; Mutation; Neonates; Neuropeptides; Newborn babies; Newborn infants; Peptidase; Peptidases; Peptides; Point Mutation; Proteases; Proteins; Rodents; Serine; Sex differences; Signaling; SUMO protein; Therapeutic applications; Type 2 diabetes; Weaning; Australia; New South Wales Australia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0078378

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.