FVB-hHTT Q150 KI Mice

Catalog Number: I001019

Strain Name: FVB/NJCya-Htttm1(hHTT*Q150)/Cya

Genetic Background: FVB/NJCya

Reproduction: Heterozygote × WT

 

Strain Description

Huntingtin (HTT) is a disease-associated gene widely expressed in various tissues and organs, including the central nervous system, and is essential for normal development. The coding region of the HTT gene contains a polymorphic trinucleotide (cytosine-adenine-guanine, CAG) repeat sequence near its 5' end, which forms a polyglutamine (polyQ) tract during translation. Huntington's disease is a neurodegenerative disorder characterized by the loss of striatal neurons, caused by the aberrant expression of the CAG repeat sequence in the HTT gene. When the CAG repeat is expanded beyond 35 copies, it leads to abnormal polyQ expansion, resulting in incorrect folding of HTT protein fragments, dysregulation of protein-protein interactions, and accumulation in the cell nucleus and neuronal terminals, ultimately affecting neural signaling, intracellular protein transport, and mitochondrial function[1]. Currently, there are no effective drugs or methods to prevent or treat Huntington's disease, and there is a great need for further research into its mechanisms and the development of therapeutic approaches[2].

This strain is an hHTT Q150 knock-in mouse model generated by gene editing technology, in which a mutated human HTT gene sequence carrying 150 CAG repeats is inserted into the mouse genome. Literature reports have shown that these mice exhibit pathological features and functional impairments characteristic of Huntington's disease, and are suitable for developing and screening therapeutic drugs for Huntington's disease as well as for safety evaluation. The heterozygous FVB-hHTT Q150 KI mice are viable and fertile.

Strain Strategy

A mutated human HTT gene sequence carrying 150 CAG repeats was knocked into the mouse Htt gene Exon 1.


Strain Application

  • Development and screening of therapeutic drugs for Huntington's disease;
  • Evaluation of therapeutic drug efficacy and safety for Huntington's disease;
  • Research on the pathogenesis of Huntington's disease.

 

Validation Data

1. Behavioral Testing: Grip Strength Test

a. 2-month-old



Figure 1. The force for WT and hHTT Q150 KI mice in the grip strength test. Data were analyzed using unpaired t-test; "ns" indicates no significant differences.

Indications:

No significant alterations in force across all models.

 

b. 3-month-old



Figure 2. The force for WT and hHTT Q150 KI mice in the grip strength test. Data were analyzed using unpaired t-test; "ns" indicates no significant differences.

Indications:

No significant alterations in force across all models.

 

2. Behavioral Testing: Open Field Test

a. 2-month-old

  • Travel Distance & Central Area Time Ratio

Figure 3. The travel distance (A-C) and central area time ratio (D-F) for WT and hHTT Q150 KI mice in open field test. Data were analyzed using unpaired t-test; "ns" indicates no significant differences, **p < 0.01, ***p < 0.001.

Indications:

(A-C) No significant alterations in travel distance across all models.

(D-F) For female and sex-mixed comparisons, hHTT Q150 KI exhibited a significant rise in the central time ratio. This may suggest increased activity levels in HTT mice compared to WT controls, as similar behavioral patterns have been documented in other Cyagen mouse models of hyperactivity. It could also imply that the HTT mice are experiencing cognitive impairment, given that spatial differentiation is a component of cognitive functions, and mice typically avoid traveling in the central area of the open field arena, which is reflected in the WT control behavioral pattern. Both types of abnormalities (hyperactivity and cognitive impairments) have been noted in previous studies on HTT mouse models (Shenoy et al., 2022) [4].

 

  • Central Speed & Peripheral Speed



Figure 4. The central speed (A-C) and peripheral speed (D-F) for WT and hHTT Q150 KI mice in open field test. Data were analyzed using unpaired t-test; "ns" indicates no significant differences.

Indications:

(A-C) No significant alterations in central speed across all models.

(D-F) No significant alterations in peripheral speed across all models.

 

b. 3-month-old

  • Travel Distance & Central Area Time Ratio


Figure 5. The travel distance (A-C) and central area time ratio (D-F) for WT and hHTT Q150 KI mice in open field test. Data were analyzed using unpaired t-test; "ns" indicates no significant differences, **p < 0.01, ***p < 0.001.

Indications:

(A-C) No significant alterations in travel distance across all models.

(D-F) For female and sex-mixed comparisons, hHTT Q150 KI exhibited a significant rise in the central time ratio. This may suggest increased activity levels in HTT mice compared to WT controls, as similar behavioral patterns have been documented in other Cyagen mouse models of hyperactivity. It could also imply that the HTT mice are experiencing cognitive impairment, given that spatial differentiation is a component of cognitive functions, and mice typically avoid traveling in the central area of the open field arena, which is reflected in the WT control behavioral pattern. Both types of abnormalities (hyperactivity and cognitive impairments) have been noted in previous studies on HTT mouse models (Shenoy et al., 2022) [4].

 

  • Central Speed & Peripheral Speed


Figure 6. The central speed (A-C) and peripheral speed (D-F) for WT and hHTT Q150 KI mice in open field test. Data were analyzed using unpaired t-test; "ns" indicates no significant differences.

Indications:

(A-C) For the female comparison, hHTT Q150 KI exhibited a significant decrease in central speed

(D-F) For the sex-mixed comparison, hHTT Q150 KI exhibited a significant decrease in peripheral speed.

 

3. Behavioral Testing: Rotarod Test (3-month-old)


Figure 7. The latency for WT and hHTT Q150 KI mice in rotarod test. Data were analyzed using unpaired t-test; "ns" indicates no significant differences, **p < 0.01, ***p < 0.001, ****p < 0.0001.

Indications:

Compared to WT, hHTT Q150 KI showed a significant decrease in latency, regardless of sex or sex-mixed comparisons, indicating impairments in locomotor activity and coordination.

 

4. Grip strength, rotarod, and open field test (14-month-old)

Figure 8. The grip strength, rotarod, and open field analysis of hHTT-Q150 KI mice at 14 months.

Compared to WT mice, both male and female hHTT-Q150 mice exhibited decreased grip strength and reduced latency on the rotarod, indicating impaired locomotor activity and coordination.

Additionally, the reduction in distance traveled and the percentage of time spent in the center further confirm deficits in locomotor activity and an increase in anxiety levels.


References
[1]Walker FO. Huntington's disease. Lancet. 2007 Jan 20;369(9557):218-28.
[2]McColgan P, Tabrizi SJ. Huntington's disease: a clinical review. Eur J Neurol. 2018 Jan;25(1):24-34.
[3]Crook ZR, Housman D. Huntington's disease: can mice lead the way to treatment? Neuron. 2011 Feb 10;69(3):423-35.
[4]Shenoy SA, Zheng S, Liu W, Dai Y, Liu Y, Hou Z, Mori S, Tang Y, Cheng J, Duan W, Li C. A novel and accurate full-length HTT mouse model for Huntington's disease. Elife. 2022 Jan 13;11:e70217.