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B6RG-Fah-KO Mouse
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B6RG-Fah-KO Mouse
製品名
B6RG-Fah-KO Mouse
製品ID
I001126
系統名
C57BL/6JCya-Fahem1Rag2em1Il2rgem1/Cya
背景情報
C57BL/6JCya
状況
このマウス系統を論文で使用する場合は、「B6RG-Fah-KO Mouse（カタログ番号I001126）はサイアジェンから購入しました。」と引用してください。
Other Immunodeficient Mice
製品タイプ
年齢
遺伝子型
性別
数量
標準的な配送方法では、少なくとも3匹のヘテロ接合体キャリアを保証しています。ホモ接合体キャリアや指定された性別の個体の繁殖サービスも利用可能です。
お見積もりについてはこちらまでご連絡ください
Other Immunodeficient Mice
基本情報
検証 Data
関連リソース
基本情報
遺伝子別名
swst, gc, p64, [g]c, CD132, gamma(c), Rag-2
染色体
Chr 7, Chr X, Chr 2
MGI ID
さらに
系統詳細
The FAH gene encodes fumarylacetoacetate hydrolase (FAH), an enzyme abundant in the liver and kidneys and involved in the final step of tyrosine degradation. Genetic changes in the FAH gene can lead to various health conditions, with the most relevant disease being Tyrosinemia Type I (HT1). This metabolic disorder, caused by mutations in the FAH gene, leads to the accumulation of toxic substances in the body, resulting in liver and kidney problems as well as other complications. Tyrosinemia Type I (HT1) is an autosomal recessive disorder resulting from the deficiency or dysfunction of FAH. Normally, tyrosine is ultimately metabolized to fumarylacetoacetate and acetoacetate. However, when the FAH gene is deficient, toxic fumarylacetoacetate and maleylacetoacetate accumulate, and secondary toxic metabolites such as succinylacetone are produced, which cause damage to the liver and kidneys. In the early stages, liver damage can lead to liver failure and cirrhosis, while kidney damage may result in rickets and developmental delays [1-2].
The IL2RG gene, also known as the CD132 gene, encodes the interleukin-2 receptor gamma chain (IL-2Rγ), which is a critical signaling component of several interleukin receptors and a common receptor subunit for many important immune factors, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. These interleukin receptors are located on the surface of immune cells, and when one of these interleukins binds to its receptor, it triggers a cascade of chemical reactions within the cell, promoting cell growth and division. Therefore, the interleukin-2 receptor gamma chain is also referred to as the common gamma chain (γc). Mutations in the IL2RG gene in humans can lead to X-linked severe combined immunodeficiency (X-SCID). This condition is characterized by the lack of T cells and natural killer cells and the dysfunction of B cells, making patients extremely susceptible to recurrent infections and preventing them from surviving beyond infancy [3-4]. In mice, knockout of the Il2rg gene leads to severe deficiencies of B cells, T cells, and NK cells in the bone marrow, peripheral blood, and spleen, resulting in a phenotype of severe immunodeficiency [4].
The RAG2 gene encodes a protein that, together with the RAG1 protein, forms the RAG complex, which plays a crucial role in V(D)J recombination during the maturation of B and T cells. It not only participates in catalyzing the reaction but also regulates the reaction by controlling access to specific gene loci [5]. Lack of functional RAG2 protein can also lead to severe combined immunodeficiency (SCID). The loss of the Rag2 gene in mice results in the absence of V(D)J recombination, which blocks the differentiation, development, and maturation of T and B cells, ultimately causing a severe combined immunodeficiency-like phenotype [6].
B6RG-Fah-KO mice are obtained by crossing Fah KO mice (Catalog No.: C001273) with B6RG mice (Rag2 and Il2rg double knockout mice, Catalog No.: C001367). Research shows that B6RG-Fah-KO mice (triple knockout of Fah, Rag, and Il2rg), developed by mating Fah KO mice with Rag2 KO and Il2rg KO mice, can be used to study human hepatocyte regeneration. After transplantation of human hepatocytes, these mice can develop "humanized livers" [7], which are of significant importance for research in liver biology, stem cells, infectious diseases, metabolism, and gene therapy.
参考文献
Morrow G, Angileri F, Tanguay RM. Molecular Aspects of the FAH Mutations Involved in HT1 Disease. Adv Exp Med Biol. 2017;959:25-48.
Frequent mutation reversioninversely correlates with clinical severity in a genetic liver disease, hereditary tyrosinemia.
Spolski R, Li P, Leonard WJ. Biology and regulation of IL-2: from molecular mechanisms to human therapy. Nat Rev Immunol. 2018 Oct;18(10):648-659.
Cao X, Shores EW, Hu-Li J, Anver MR, Kelsall BL, Russell SM, Drago J, Noguchi M, Grinberg A, Bloom ET, et al. Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. Immunity. 1995 Mar;2(3):223-38.
Schatz DG. V(D)J recombination. Immunol Rev. 2004 Aug;200:5-11.
Hao Z, Rajewsky K. Homeostasis of peripheral B cells in the absence of B cell influx from the bone marrow. J Exp Med. 2001 Oct 15;194(8):1151-64.
Grompe M. Fah Knockout Animals as Models for Therapeutic Liver Repopulation. Adv Exp Med Biol. 2017;959:215-230.
系統作製戦略
Crossing Fah KO mice (Catalog No.: C001273) with B6RG mice (Rag2 and Il2rg double knockout mice, Catalog No.: C001367).
適用分野
Research on tyrosinemia Type I (HT1);
Research on liver biology and liver-related drugs;
Human liver regeneration and reconstruction;
Stem cell, infectious disease, metabolism, and gene therapy.
検証 Data
1. Gene Expression
The mRNA expression levels of mouse-derived Fah in the kidney and liver tissues of B6RG-Fah-KO mice and wild-type (WT) mice were detected using RT-qPCR. The results showed that mouse Fah mRNA expression was detectable in the liver and kidney tissues of WT mice, whereas no mouse-derived Fah mRNA expression was detected in the liver and kidney tissues of B6RG-Fah-KO mice.
Figure 1. Detection of mouse Fah gene expression in the kidney and liver of B6RG-Fah-KO mice and wild-type (WT) mice (6 weeks of age, WT: C57BL/6J; B6RG-Fah-KO: Fah-/-Il2rg-/-Rag2-/-, n = 3 ♀). Data are presented as Mean±SD.
2. Phenotypic Characterization of B6RG-Fah-KO Mice Following NTBC Withdrawal
（1）Experimental Design for Phenotypic Assessment Following NTBC Withdrawal
Wild-type (WT) and B6RG-Fah-KO mice were included in the study. The WT group consisted of 5 males and 5 females, while the B6RG-Fah-KO group consisted of 9 males and 8 females. B6RG-Fah-KO mice received continuous administration of nitisinone (NTBC) from the initiation of breeder mating until 8 weeks of age, at which point NTBC treatment was discontinued.
Body weight was monitored weekly from 6 to 12 weeks of age. Serum biochemical parameters, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (T-BIL), were measured every two weeks. At 12 weeks of age, blood samples were collected, followed by terminal tissue collection 3 days later. Serum samples were used for mass spectrometry-based quantification of tyrosine levels, while liver and kidney tissues were collected for hematoxylin and eosin (H&E) staining and histopathological analysis.
Figure 2. Schematic diagram of the experimental design for NTBC withdrawal and phenotypic monitoring in B6RG-Fah-KO mice and wild-type (WT) mice (WT: C57BL/6J, n=5♂/5♀; B6RG-Fah-KO (Fah-/-Il2rg-/-Rag2-/-): n=9♂/8♀).
（2）Growth Curves and Survival Analysis
Body weight was monitored weekly from 6 to 12 weeks of age in WT and B6RG-Fah-KO mice. Compared with age-matched WT mice, both male and female B6RG-Fah-KO mice exhibited lower body weights. Following NTBC withdrawal at 8 weeks of age, body weight further declined in B6RG-Fah-KO mice. Survival monitoring showed that male B6RG-Fah-KO mice began to die on Day 27 after NTBC withdrawal, with a cumulative mortality of 5/9, whereas female B6RG-Fah-KO mice began to die on Day 14 after NTBC withdrawal, with a cumulative mortality of 4/8.
Figure 3. Growth curves and survival of B6RG-Fah-KO mice and wild-type (WT) mice (WT: C57BL/6J, n=5♂/5♀; B6RG-Fah-KO: Fah-/-Il2rg-/-Rag2-/-, n=9♂/8♀). Data are presented as mean±SD. *P<0.05, **P<0.01, and ***P<0.001 indicate comparisons between male B6RG-Fah-KO mice and male WT mice; #P<0.05, ##P<0.01, and ###P<0.001 indicate comparisons between female B6RG-Fah-KO mice and female WT mice.
（3）Serum Biochemical Analysis of Liver Function Markers (T-BIL, ALT, and AST)
Serum levels of total bilirubin (T-BIL), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were measured in WT and B6RG-Fah-KO mice. Following NTBC withdrawal at 8 weeks of age, serum T-BIL, ALT, and AST levels were elevated in B6RG-Fah-KO mice compared with WT mice, indicating liver injury. Notably, serum ALT levels in female B6RG-Fah-KO mice decreased at 12 weeks of age. Combined with the subsequent liver histopathological findings, this decrease was considered to reflect progression to more severe liver injury rather than recovery.
Figure 4. Serum liver function markers (T-BIL, ALT, and AST) in B6RG-Fah-KO mice and wild-type (WT) mice (WT: C57BL/6J, n=5♂/5♀; B6RG-Fah-KO: Fah-/-Il2rg-/-Rag2-/-, n=9♂/8♀). Data are presented as mean±SD. *P<0.05, **P<0.01, and ***P<0.001 indicate comparisons between male B6RG-Fah-KO mice and male WT mice; #P<0.05, ##P<0.01, and ###P<0.001 indicate comparisons between female B6RG-Fah-KO mice and female WT mice.
（4）Histopathological Analysis of Liver and Kidney
Following NTBC withdrawal, both male and female B6RG-Fah-KO mice developed pronounced pathological changes in the liver and kidneys. In the liver, the major pathological findings included hepatocyte apoptosis/necrosis, vacuolar degeneration, inflammatory cell infiltration, Kupffer cell hyperplasia, and fibrosis. In the kidneys, inflammatory cell infiltration accompanied by fibrosis was observed.
Figure 5. Histopathological changes in the liver of male B6RG-Fah-KO mice following NTBC withdrawal. Hepatic tissue from male B6RG-Fah-KO mice following NTBC withdrawal exhibited single-cell apoptosis (black arrows), vacuolar degeneration (red arrows), inflammatory cell infiltration (blue arrows), Kupffer cell hyperplasia (yellow arrows), and fibrosis (green arrows).
Figure 6. Histopathological changes in the liver of female B6RG-Fah-KO mice following NTBC withdrawal. Hepatic tissue from female B6RG-Fah-KO mice following NTBC withdrawal exhibited single-cell apoptosis (black arrows), vacuolar degeneration (red arrows), inflammatory cell infiltration (blue arrows), Kupffer cell hyperplasia (yellow arrows), and fibrosis (green arrows).
Figure 7. Histopathological changes in the kidney of male B6RG-Fah-KO mice following NTBC withdrawal. Renal tissue from male B6RG-Fah-KO mice following NTBC withdrawal exhibited inflammatory cell infiltration (black arrows), mild degeneration of renal tubular epithelial cells (blue arrows), and mild thickening of the glomerular mesangium (yellow arrows).
Figure 8. Histopathological changes in the kidney of female B6RG-Fah-KO mice following NTBC withdrawal. Renal tissue from female B6RG-Fah-KO mice following NTBC withdrawal exhibited inflammatory cell infiltration (black arrows), mild degeneration of renal tubular epithelial cells (blue arrows), and mild thickening of the glomerular mesangium (yellow arrows).
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