B6-hCALCRL Mice

Catalog Number: C001497

Genetic Background: C57BL/6JCya

Reproduction: Homozygote x Homozygote

Strain Description

Calcitonin receptor-like receptor (CALCRL) is a seven-transmembrane G protein-coupled receptor encoded by the CALCRL gene. It mediates the pleiotropic effects of calcitonin gene-related peptide (CGRP) and adrenal medullary peptide (ADM), two structurally related neuropeptides that are potent vasodilators and play an important role in blood pressure regulation ^[1]. In addition, CALCRL is involved in various other biological processes, including cell proliferation, cell death regulation, vascular biology, and inflammation ^[2]. CALCRL is currently being investigated as a new target for the treatment of migraine ^[3]. In solid tumors, antibodies that target CALCRL have been shown to reduce tumor growth by either disrupting angiogenesis or by directly inhibiting cancer cell proliferation ^[4]. CALCRL is also expressed in normal CD34+ hematopoietic progenitor cells, and CGRP and ADM can directly stimulate these cells to form colonies in vitro, suggesting a role for CALCRL in physiological bone marrow generation ^[5].

This strain represents a humanized mouse model of the Calcrl gene. Using gene editing technology, the sequence encoding the extracellular domain of the mouse Calcrl gene was replaced with the corresponding sequence from the human CALCRL gene. This model can be used to study the mechanisms of various physiological and pathological processes, such as blood pressure regulation, cell proliferation, cell death, vascular biology, physiological bone marrow generation, inflammation, and tumor growth, as well as the development of CALCRL-targeted migraine drugs and therapies. Homozygous B6-hCALCRL mice are viable and fertile.

Strain Strategy

Figure 1. Schematic representation of the gene editing strategy for generating B6-hCALCRL mice. Using gene editing technology, the sequence encoding the extracellular domain (amino acids 23 to 145) of the endogenous mouse Calcrl gene was replaced with the corresponding sequence (amino acids 23 to 146) from the human CALCRL gene, while preserving the sequence encoding the signal peptide (amino acids 1 to 22) of the mouse Calcrl gene.

Validation Data

1. Detection of human CALCRL gene expression

Figure 2. Expression of the human CALCRL gene (hCALCRL) in the spleen and lung of 5-week-old wild-type mice (B6J) and B6-hCALCRL mice. Expression of human CALCRL was assessed by real-time quantitative PCR (RT-qPCR) using human CALCRL gene-specific primers. Results showed that B6-hCALCRL mice successfully expressed human CALCRL gene in the spleen and lung.

 

2. Detection of mouse Calcrl gene expression

Figure 3. Expression of the mouse Calcrl gene (mCalcrl) in the spleen and lung of 5-week-old wild-type mice (B6J) and B6-hCALCRL mice. Expression of mouse Calcrl was assessed by real-time quantitative PCR (RT-qPCR) using mouse Calcrl gene-specific primers. Results showed that B6-hCALCRL mice did not express mouse Calcrl gene in the spleen and lung.

Reference

[1] Brain SD, Williams TJ, Tippins JR, Morris HR, MacIntyre I. Calcitonin gene-related peptide is a potent vasodilator. Nature. 1985 Jan 3-9;313(5997):54-6.

[2] Russell FA, King R, Smillie SJ, Kodji X, Brain SD. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev. 2014 Oct;94(4):1099- 142.

[3] Hershey AD. CGRP - The Next Frontier for Migraine. N Engl J Med. 2017 Nov 30;377(22):2190-2191.

[4] Toda M, Suzuki T, Hosono K, Hayashi I, Hashiba S, Onuma Y, Amano H, Kurihara Y, Kurihara H, Okamoto H, Hoka S, Majima M. Neuronal system-dependent facilitation of tumor angiogenesis and tumor growth by calcitonin gene-related peptide. Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13550-5.

[5] Chute JP, Muramoto GG, Dressman HK, Wolfe G, Chao NJ, Lin S. Molecular profile and partial functional analysis of novel endothelial cell-derived growth factors that regulate hematopoiesis. Stem Cells. 2006 May;24(5):1315-27.