B6.129S1-Htt^tm1.1Mfc/190ChdiJ

Stock number: 029928
Product name: zQ175 neo-deleted knock-in , zQ175DN KI , B6J.zQ175DN KI
Research areas: Neurobiology Research, Research Tools

Description

The zQ175 neo-deleted knock-in allele (zQ175DN KI) has the mouse Htt exon 1 replaced by the human HTT exon 1 sequence with a ~190 CAG repeat tract. These B6J.zQ175DN KI mice (Stock No. 029928) are useful for studying Huntington's disease pathogenesis and for the assessment of potential therapeutic interventions.
This zQ175DN KI allele is the same design as the zQ175 KI allele (Stock No. 027410), with the exception that this zQ175DN KI has had the floxed neo cassette removed. It is not specifically characterized if deletion of the neo cassette alters the zQ175DN KI phenotype compared to the zQ175 KI phenotype.

As of November 2017, the Stock No. 029928 live colony has approximately 180-220 trinucleotide repeats (see Detailed Description section for more Trinucleotide Scoring and Range information).

This strain ships with remnant UID MiniMax microchips implanted subcutaneously in the back. For more information on these RFID chips, including our FAQ, please visit our Mouse Identification page.

Detailed description

Stock No. 029928 was formerly associated with CHDI Foundation colony Stock No. 370832.

This zQ175 neo-deleted knock-in allele (zQ175DN KI) is the same design as the zQ175 knock-in allele (zQ175 KI; Stock No. 027410), with the exception that this zQ175DN KI has had the floxed neo cassette removed. It is not specifically characterized if deletion of the neo cassette alters the zQ175DN KI phenotype compared to the zQ175 KI phenotype. For possible phenotype of zQ175DN KI mice, please see Stock No. 027410.

Trinucleotide Repeat monitoring:
In these mutant mice, the trinucleotide repeat number is subject to germline and somatic instability, and may expand or contract. When using lines with unstable trinucleotide repeat length, it is strongly recommended the repeat number be quantified in all the experimental animals; all animals in all experimental groups should carry comparable trinucleotide repeat sizes. Trinucleotide repeat sizing of HD mice should be done using high-resolution methods; as assays based on agarose gel electrophoresis typically do not provide sufficient resolution to accurately measure trinucleotide repeat numbers. If labs do not have access to the appropriate equipment for determining repeat length, trinucleotide repeats can be evaluated on a fee-for-service basis by TransnetYX, Inc.

Stock No. 029928 B6.129S1-Htt^tm1.1mfc/190ChdiJ - Trinucleotide Scoring and Range [November 2024]:
 As of November 2017, the Stock No. 029928 live colony has 180-220 trinucleotide repeats.
 In 2024, The Jackson Laboratory scoring of this strain's trinucleotide repeat values was changed to Transnetyx following their acquisition of Laragen. Subsequently, The Jackson Laboratory Genetic Quality Control group and Transnetyx performed side-by-side trinucleotide repeat value analyses of the same heterozygous mouse samples (representing several different pedigrees within the live colony) via the Laragen protocol versus the Transnetyx protocol. For Stock No. 029928, more than 75 mouse samples were analyzed - this showed the Laragen score averaging 2.05 trinucleotide repeats higher than the same sample scored via Transnetyx. Based on these analyses, The Jackson Laboratory has adjusted the trinucleotide score range we use for Stock No. 029928 heterozygous breeder mice from 180-190 trinucleotide repeats via Laragen protocol to 178-188 trinucleotide repeats via Transnetyx "GM CAG" quantification protocol, and heterozygous distribution mice from 180-220 trinucleotide repeats via Laragen protocol to 178-218 trinucleotide repeats via Transnetyx "GM CAG" quantification protocol [November 2024].

This Huntington's disease mouse model is available by way of a collaborative effort between CHDI Foundation, Dr. Scott Zeiltin (University of Virginia), Dr. Marie-Francoise Chesselet (University of California, Los Angeles), PsychoGenics, Inc. and The Jackson Laboratory.

Development

Stock No. 029928 zQ175 neo-deleted knock-in (or zQ175DN KI) mice were formerly associated with CHDI Foundation colony Stock No. 370832.

First, the zQ175 knock-in allele (zQ175 KI) was derived from a spontaneous expansion of the CAG copy number in CAG140 knock-in (CAG 140 KI) mice as described below. The zQ175 knock-in (zQ175 KI) mouse was generated by Drs. Scott Zeitlin (University of Virginia) and Marie-Francoise Chesselet (University of California, Los Angeles) and colleagues. A fragment extending from 18 bp upstream of huntingtin (Htt; HD or Hdh) exon 1 to 100 bp into intron 1 was replaced with human HTT sequence containing 140 repeats of a pure CAG tract [(CAG)nCAACAG, encoding polyglutamine]. A floxed neo cassette was originally found 1.3 kbp upstream of exon 1. The targeting vector was microinjected into 129S1/Sv-Oca2⁺ Tyr⁺ Kitl⁺-derived W9.5/W95 embryonic stem (ES) cells. While backcrossing onto C57BL/6J at PsychoGenics, germline expansions of the CAG tract led to the identification of a mouse with 175 CAG repeats. This mouse was selectively bred to create a new subline, named zQ175 (with the letter z used to identify that the line was derived from a line created by Scott Zeitlin). Subsequently, the CAG repeat number in zQ175 expanded further, and a line was selectively stabilized with ~190 CAG repeats.

In ~2013, the floxed neo cassette was removed from the germline via breeding to Zp3-Cre transgenic mice (Stock No. 003651). The resulting mice, called zQ175 neo-deleted knock-in (or zQ175DN KI), were then bred to C57BL/6J mice to remove the Zp3-Cre transgene.

Of note, this zQ175DN KI mouse line is identical in construct to CAG 140 KI mice except for CAG tract size (and the deletion of the floxed neo cassette).

The zQ175DN KI mice have been backcrossed with C57BL/6J inbred mice (Stock No. 000664) for several generations to create the C57BL/6J-congenic colony (B6J.zQ175DN KI), called CHDI Foundation colony Stock No. 370832.

In 2017, heterozygous males from generation N11 with ~190 CAG repeat length and black coat color were sent from the CHDI Foundation colony to The Jackson Laboratory Repository, from which B6J.zQ175DN KI heterozygotes will be available as Stock No. 029928.

Stock No. 029928 B6.129S1-Htt^tm1.1mfc/190ChdiJ - Trinucleotide Scoring and Range [November 2024]:
 As of November 2017, the Stock No. 029928 live colony has 180-220 trinucleotide repeats.
 In 2024, The Jackson Laboratory scoring of this strain's trinucleotide repeat values was changed to Transnetyx following their acquisition of Laragen. Subsequently, The Jackson Laboratory Genetic Quality Control group and Transnetyx performed side-by-side trinucleotide repeat value analyses of the same heterozygous mouse samples (representing several different pedigrees within the live colony) via the Laragen protocol versus the Transnetyx protocol. For Stock No. 029928, more than 75 mouse samples were analyzed - this showed the Laragen score averaging 2.05 trinucleotide repeats higher than the same sample scored via Transnetyx. Based on these analyses, The Jackson Laboratory has adjusted the trinucleotide score range we use for Stock No. 029928 heterozygous breeder mice from 180-190 trinucleotide repeats via Laragen protocol to 178-188 trinucleotide repeats via Transnetyx "GM CAG" quantification protocol, and heterozygous distribution mice from 180-220 trinucleotide repeats via Laragen protocol to 178-218 trinucleotide repeats via Transnetyx "GM CAG" quantification protocol [November 2024].

Allele

Symbol: Htt^tm1.1Mfc
Name: targeted mutation 1.1, Marie-Francoise Chesselet
MGI accession ID: MGI:5789600
Generation method: Targeted
Attributes: Humanized sequence
Synonyms: Htt^Q175neo-; zQ175^deltaNeo
Marker symbol: Htt
Marker name: huntingtin
Marker synonyms: C430023I11Rik; Hd; Hdh; htt; IT15; LOMARS
Chromosome: 5
Strain of origin: 129S1/Sv-Oca2⁺ Tyr⁺ Kitl⁺
Molecular note: A fragment extending from 18 bp upstream of the polyglutamine stretch in exon 1 to 100 bp into intron 1 was replaced with human HTT sequence containing 140 CAG repeats. A floxed neo cassette 1.3 kb upstream of exon 1 has been deleted. The repeat number is not stable and may expand or contract.