B6-hDPP4(line 2) Mice

Catalog Number: I001188

Strain Name: C57BL/6JCya-Dpp4em2(hDPP4)/Cya

Genetic Background: C57BL/6JCya

 

Strain Description

The DPP4 gene (CD26) encodes dipeptidyl peptidase 4, an intrinsic type II transmembrane glycoprotein and a serine exopeptidase involved in glucose and insulin metabolism and immune regulation. The DPP4 protein is a functional receptor for the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). The spike protein of MERS-CoV binds to DPP4, mediating the virus's attachment to host cells and promoting virus-cell fusion, thereby initiating infection [1-2]. Studies have found that the DPP4 protein may interact with the S1 domain of the spike glycoprotein of COVID-19, aiding in enhancing the transmission efficiency of viral particles [3]. Experimental evidence has shown that hDPP4 transgenic mice infected with MERS-CoV experience high mortality and severe pneumonia [4]. These mice infected with Manis javanica HKU4-related coronavirus (MjHKU4r-CoV-1) develop mild to moderate pulmonary histological damage [5]. Thus, gene-edited mice expressing human DPP4 protein are important tools for studying coronavirus infections. Additionally, DPP4 expression is severely dysregulated in diseases such as inflammation, cancer, obesity, and diabetes. DPP4 is highly expressed in the intestine, where it selectively cleaves N-terminal dipeptides from various substrates, including incretins, to inactivate multiple bioactive peptides. Since incretins like glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are crucial for regulating postprandial insulin secretion, inhibiting DPP4 to elevate endogenous GLP-1 and GIP levels to increase insulin levels has become an important treatment method for type 2 diabetes (T2D) [6].

The B6-hDPP4(line 2) mouse is a humanized model constructed by gene editing technology to replace a partial region of the mouse Dpp4 gene with the human DPP4 gene CDS sequence. This model can be used to study the infection mechanisms of viruses such as MERS-CoV and COVID-19, as well as to develop related virus vaccines. Additionally, this model can be utilized to develop DPP4 inhibitor therapies. Similar models include the B6-hDPP4(line 1) mouse (Catalog ID: I001187), constructed on the C57BL/6NCya background strain, which replaces the sequence encoding aa.29~aa.760 of the mouse Dpp4 gene with the human DPP4 gene CDS sequence (aa.29-766), and the BALB/c-hDPP4(line 2) mouse (Catalog ID: I001189), constructed on the BALB/cAnCya background strain. These models meet the experimental needs of different strain backgrounds.

Strain Strategy


Figure 1. Gene editing strategy of B6-hDPP4(line 2) mice. From p.S29 to partial intron 2 was replaced with the Human DPP4 CDS (aa.29-766)-rBG pA cassette. The murine topological domain and transmembrane (aa.1-28) were remained.

Application

  • Development of DPP4 inhibitor therapies;
  • Research on Middle East Respiratory Syndrome (MERS-CoV) infection;
  • Research on Severe Acute Respiratory Syndrome (SARS-CoV) infection.

 

References

[1]Raj VS, Mou H, Smits SL, Dekkers DH, Müller MA, Dijkman R, Muth D, Demmers JA, Zaki A, Fouchier RA, Thiel V, Drosten C, Rottier PJ, Osterhaus AD, Bosch BJ, Haagmans BL. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature. 2013 Mar 14;495(7440):251-4.
[2]Lu G, Hu Y, Wang Q, Qi J, Gao F, Li Y, Zhang Y, Zhang W, Yuan Y, Bao J, Zhang B, Shi Y, Yan J, Gao GF. Molecular basis of binding between novel human coronavirus MERS-CoV and its receptor CD26. Nature. 2013 Aug 8;500(7461):227-31.
[3]Vankadari N, Wilce JA. Emerging WuHan (COVID-19) coronavirus: glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26. Emerg Microbes Infect. 2020 Mar 17;9(1):601-604.
[4]Agrawal AS, Garron T, Tao X, Peng BH, Wakamiya M, Chan TS, Couch RB, Tseng CT. Generation of a transgenic mouse model of Middle East respiratory syndrome coronavirus infection and disease. J Virol. 2015 Apr;89(7):3659-70.
[5]Chen J, Yang X, Si H, Gong Q, Que T, Li J, Li Y, Wu C, Zhang W, Chen Y, Luo Y, Zhu Y, Li B, Luo D, Hu B, Lin H, Jiang R, Jiang T, Li Q, Liu M, Xie S, Su J, Zheng X, Li A, Yao Y, Yang Y, Chen P, Wu A, He M, Lin X, Tong Y, Hu Y, Shi ZL, Zhou P. A bat MERS-like coronavirus circulates in pangolins and utilizes human DPP4 and host proteases for cell entry. Cell. 2023 Feb 16;186(4):850-863.e16.
[6]Röhrborn D, Wronkowitz N, Eckel J. DPP4 in Diabetes. Front Immunol. 2015 Jul 27;6:386.