Targeted inactivation of Dipeptidyl Peptidase 9 enzyme activity in mice — ASN Events
  1. Schedule
  2. Session Five - Poster Session A
  3. Targeted inactivation of Dipeptidyl Peptidase 9 enzyme activity in mice

Targeted inactivation of Dipeptidyl Peptidase 9 enzyme activity in mice (#108)

Margaret G Gall 1 , Yiqian Chen 1 , Ana Julia Vieira de Ribeiro 1 , Derek Spielman 2 , Denise MT Yu 3 , Mark D Gorrell 1
  1. Centenary Institute, Newtown, NSW, Australia
  2. Faculty of Veterinary Science, University of Sydney, Sydney, NSW, Australia
  3. Children's Cancer Institute Australia, Lowy Cancer Research Centre, Sydney, NSW, Australia

The Dipeptidyl Peptidases (DPP) have emerged in recent years as interesting therapeutic targets. DPP4 is the target of a type 2 diabetes therapy in which the DPP4-selectivity of each protease inhibitory drug is essential. Dipeptidyl Peptidase 9 (DPP9) is an intracellular enzyme with roles in cell biology (Yu et al, 2006; Yao et al, 2011), however little is known about its functional significance.

To further characterise the function of this enzyme and examine the in vivo significance of DPP9 enzyme activity, a gene knock-in mouse was generated containing a point mutation. We have previously shown that substitution of the catalytic serine of DPP9 to alanine in amino acid position 729 (S729A) ablates DPP enzyme activity.

Characterisation of DPP9S729A/S729Aembryo-generated mouse embryonic fibroblasts (MEFs) and neonate DPP9S729A/S729A mouse livers confirmed the presence of DPP9 protein but the absence of DPP9 enzyme activity. This biological strategy was expected to mimic the effect of a selective DPP9 inhibitor administered from embryonic stage.

Phenotype studies revealed that, while late-stage DPP9S729A/ S729A homozygote embryos and early neonates were phenotypically indistinguishable from their wild-type littermates, most of these neonates were found dead shortly after birth. Histochemical studies of embryos and early neonates revealed an, as yet, undefined phenotype.

While further investigation is necessary, these findings suggest an important role of DPP9 enzymatic activity in early postnatal mouse survival.

  1. Yao, T.-W., W.-S. Kim, et al. (2011). "A Novel Role of Dipeptidyl Peptidase 9 in Epidermal Growth Factor Signaling." Molecular Cancer Research 9(7): 948-959.
  2. Yu, D. M. T., X. M. Wang, et al. (2006). "Extra-enzymatic functions of the dipeptidyl peptidase (DP) IV related proteins DP8 and DP9 in cell adhesion, migration and apoptosis." FEBS Journal 273(11): 2447-2461.