Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Species laboratory mouse Generation N?pN1 Generation Definitions   Donating Investigator Shihua Li,   Emory University School of Medicine

Description
Mice homozygous for this Huntingtin Associated Protein (HAP1)-deficient allele have neurodegeneration in areas of the hypothalamus that control feeding behavior, resulting in decreased feeding behavior, dehydration, hypoactivity, and death between two and 15 days after birth. No protein expression from the targeted gene is observed in brain tissue from homozygous mice. Hypothalamus tissue from HAP1-deficient homozygotes exhibit reduced levels of gamma-aminobutyric acid-A (GABA_A; a neurotransmitter associated with feeding) and tropomyosin-related kinase A receptor tyrosine kinase (TrkA; a nerve growth factor receptor associated with neurite outgrowth). Heterozygous mice are viable and fertile with no abnormalities in HAP1 expression levels, life span, behavior, and body weight. These huntingtin-associated protein-1 (HAP1) mutant mice may be useful in studying the hypothalamic neurodegeneration and loss of body weight in Huntingon's disease (HD), neurotransmitters, microtubule-dependent transporters, intracellular trafficking, receptor tyrosine kinase and neurite function, and feeding.

In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. These mice were originally published on a mixed Black Swiss and 129S6/SvEvTac genetic background. It should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.

Development
A targeting vector was designed to replace the first two exons (first 131 amino acids) of the targeted gene with a neomycin cassette. The construct was electroporated into 129S6/SvEvTac-derived TC-1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient C57BL/6 blastocysts. The resulting chimeric males were bred with Black Swiss females to generate mutant offspring. These HAP1 mutant mice were maintained on a mixed genetic background ("129S6Ev/Black Swiss" and possibly "SV129BL/6") for many generations prior to arrival at The Jackson Laboratory. Upon arrival at The Jackson Laboratory, these mice may have been bred to C57BL/6J inbred mice (Stock No. 000664) for at least one generation to establish the colony.

Control Information

	Control
	Wild-type from the colony
Considerations for Choosing Controls

Related Strains

Huntington's Disease Models

007708	B6.129-Gt(ROSA)26Sortm1(HD*103Q)Xwy/J
003454	B6.129-Htttm3Mem/J
003597	B6.129-Htttm4Mem/J
003598	B6.129-Htttm5Mem/J
016094	B6.129P2-Git2Gt(XG510)Byg/WeisJ
016522	B6.129P2-Htttm2Detl/100J
004595	B6.129P2-Htttm2Detl/150J
016521	B6.129P2-Htttm2Detl/50J
002688	B6.129S4-Htttm1Mem/J
006471	B6.Cg-Tg(HDexon1)61Gpb/J
008333	B6;129P2-Dldtm1Ptl/J
004360	B6;SJL-Tg(HD)63Aron/J
003627	B6C3-Tg(HD82Gln)81Dbo/J
002809	B6CBA-Tg(HDexon1)61Gpb/1J
002810	B6CBA-Tg(HDexon1)62Gpb/1J
006494	B6CBA-Tg(HDexon1)62Gpb/3J
016095	C.129P2(B6)-Git2Gt(XG510)Byg/WeisJ
008833	C57BL/6-Tg(Camk2a-UBB)3413-1Fwvl/J
007578	CBy.Cg-Tg(HDexon1)61Gpb/J
013732	FVB-Tg(NPEPPS)1Skar/J
004938	FVB-Tg(YAC128)53Hay/J
012630	FVB/N-Tg(GFAP-HTT*160Q)31Xjl/J
008197	FVB/N-Tg(HTT*97Q)IXwy/J
007247	FVB/N-Tg(YAC353G6)W7Hay/J
003640	FVB/NJ-Tg(YAC72)2511Hay/J
003453	STOCK Htttm2Mem/J
003455	STOCK Htttm4Mem/J
003456	STOCK Htttm5Mem/J

View Huntington's Disease Models     (28 strains)

Additional Web Information

Visit the Huntington's Diease Resource site for helpful information on Huntington's Disease and research resources.

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

NOT	Huntington Disease; HD - No similarity to the expected human disease phenotype was found.4

4 One or more human genes are associated with this human disease. The mouse genotype may involve mutations to orthologs of one or more of those genes, but the phenotype did not resemble the disease.

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Hap1^tm1Xjl/Hap1^tm1Xjl

        involves: 129S6/SvEvTac * Black Swiss

• mortality/aging
• complete postnatal lethality
  • most homozygotes die at 3 to 4 days after birth   (MGI Ref ID J:84682)
  • a few survive beyond 9 days of age, in the absence of skin, bone, or organ abnormalities   (MGI Ref ID J:84682)
  • no homozygotes survive beyond 15 days of age   (MGI Ref ID J:84682)
• growth/size phenotype
• slow postnatal weight gain
  • homozygotes fail to gain weight after birth   (MGI Ref ID J:84682)
• behavior/neurological phenotype
• *normal* behavior/neurological phenotype
  • homozygotes that survive beyond 9 days of age do not exhibit defects in movement, tactile response, or motor control   (MGI Ref ID J:84682)
• • absent gastric milk in neonates
    • mutant pups contain very little gastric milk, suggesting a feeding defect that may retard postnatal growth   (MGI Ref ID J:84682)
• nervous system phenotype
• abnormal hypothalamus morphology
  • at P1, TUNEL-positive cells are observed in the paraventricular nuclei (PVN) and the lateral hypothalamus (LH) of mutant but not wild-type mice; very few or no TUNEL-positive cells are noted in the arcuate nucleus (ARC) of mutant mice   (MGI Ref ID J:84682)
  • by P3, TUNEL-labeled cells are more widely spread in various regions of the hypothalamus which control eating, food intake, and energy metabolism, including the ventromedial hypothalamic nucleus (VMN)   (MGI Ref ID J:84682)
• neurodegeneration
  • as early as P1, homozygotes display degeneration in specific regions of the hypothalamus that control feeding behavior, as determined by TUNEL staining   (MGI Ref ID J:84682)
  • in contrast, other brain regions (e.g. cortex, striatum, cerebellum, and hippocampus) display significantly fewer TUNEL-positive cells or show no difference relative to wild-type mice   (MGI Ref ID J:84682)

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Cell Biology Research
Channel and Transporter Defects
Signal Transduction
Vesicular Trafficking

Developmental Biology Research
Perinatal Lethality
      Homozygous

Mouse/Human Gene Homologs
Huntington's disease (chorea)

Neurobiology Research
Channel and Transporter Defects
Huntington's disease
Neurodegeneration
Neurodevelopmental Defects
Neurotransmitter Receptor and Synaptic Vesicle Defects
Receptor Defects

Research Tools
Cell Biology Research
Neurobiology Research

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Hap1tm1Xjl
Allele Name		targeted mutation 1, Xiao-Jiang Li
Allele Type		Targeted (knock-out)
Common Name(s)		HAP1-;
Mutation Made By		Xiao-Jiang Li,   Emory University School of Medicine
Strain of Origin		129S6/SvEvTac
ES Cell Line Name		TC1/TC-1
ES Cell Line Strain		129S6/SvEvTac
Gene Symbol and Name		Hap1, huntingtin-associated protein 1
Chromosome		11
Gene Common Name(s)		HAP-1; HAP1-A; HAP1-B; HAP2; HIP5; HLP; hHLP1;
Molecular Note		Exons 1 and 2, which encode the first 131 amino acids, were replaced with a neomycin selection cassette. Protein was undetected in the brains of homozygous mutant mice by Western blot analysis. [MGI Ref ID J:84682]

Genotyping

Genotyping Information

Genotyping Protocols

Hap1^tm1Xjl, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Li SH; Yu ZX; Li CL; Nguyen HP; Zhou YX; Deng C; Li XJ. 2003. Lack of huntingtin-associated protein-1 causes neuronal death resembling hypothalamic degeneration in Huntington's disease. J Neurosci 23(17):6956-64. [PubMed: 12890790]  [MGI Ref ID J:84682]

Rong J; McGuire JR; Fang ZH; Sheng G; Shin JY; Li SH; Li XJ. 2006. Regulation of intracellular trafficking of huntingtin-associated protein-1 is critical for TrkA protein levels and neurite outgrowth. J Neurosci 26(22):6019-30. [PubMed: 16738245]  [MGI Ref ID J:128472]

Sheng G; Chang GQ; Lin JY; Yu ZX; Fang ZH; Rong J; Lipton SA; Li SH; Tong G; Leibowitz SF; Li XJ. 2006. Hypothalamic huntingtin-associated protein 1 as a mediator of feeding behavior. Nat Med 12(5):526-33. [PubMed: 16604089]  [MGI Ref ID J:109572]

Additional References

Hap1^tm1Xjl related

Sheng G; Xu X; Lin YF; Wang CE; Rong J; Cheng D; Peng J; Jiang X; Li SH; Li XJ. 2008. Huntingtin-associated protein 1 interacts with Ahi1 to regulate cerebellar and brainstem development in mice. J Clin Invest 118(8):2785-95. [PubMed: 18636121]  [MGI Ref ID J:140869]

Wu LL; Fan Y; Li S; Li XJ; Zhou XF. 2010. Huntingtin-associated protein-1 interacts with pro-brain-derived neurotrophic factor and mediates its transport and release. J Biol Chem 285(8):5614-23. [PubMed: 19996106]  [MGI Ref ID J:159764]

Health & husbandry

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Health & Colony Maintenance Information

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, RG10/RG30.

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, heterozygous mice are bred to wildtype siblings. Homozygous mice die between 2 and 15 days after birth.

Purchasing information

Pricing, Supply Level & Notes, Controls

General Supply Notes

• This strain is included in the Induced Mutant Resource Colony collection.

Control Information

	Control
	Wild-type from the colony
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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