Description

Strain Information

Former Names B6 x C57BLKS-Pitx3ak/J    (Changed: 04-MAY-05 ) Type Mutant Strain; Spontaneous Mutation; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse Generation N6p

Description
Mice homozygous for the Pitx3^ak mutation exhibit microphthalmia (small eyes) and aphakia (no lens) related to arrested lens development. The mesencephalic dopamine system is malformed and as a result homozygotes fail to develop dopaminergic neurons of the substantia nigra (Smidt et al., 2004). Homozygotes display sensorimotor deficits specific to the nigrostriatal pathway such as the challenge beam and pole test and the test for spontaneous exploratory activitiy in a cylinder. These deficits can be reversed by L-DOPA administration (Hwang et al., 2005). This mutant mouse strain may be useful in studies of Parkinson's disease.

Development
The aphakia allele arose spontaneously in 1981 on the 129S1/Sv-p⁺ Tyr⁺ Kitl^Sl-J/J strain. A female with a small right eye was mated to a male with small left eye (male 1). The mating produced greater than 50% bilaterally aphakic pups. As a result of poor breeding on the original129S1 background, male 1 was mated to a C57BLKS/J female. The one F1 aphakic female produced was used to build the colony. The colony was maintained by occasional crossing to C57BLKS/J (Varnum et al. 1968). This strain was cryopreserved in 1984 using homozygous males at generation N5F39 or N5F40 bred to C57BL/6J females. The strain was cryo-recovered in 2005.

Control Information

	Control
	Heterozygote from the colony
Considerations for Choosing Controls

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

	Anterior Segment Mesenchymal Dysgenesis; ASMD - Models with phenotypic similarity to human disease where etiologies involve orthologs.1
	Parkinson Disease; PD - Models with phenotypic similarity to human disease where etiologies are distinct.2
	Parkinson Disease; PD - Models with phenotypic similarity to human disease where etiologies involve orthologs.1

1 Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s). 2 Human genes are associated with this disease. Orthologs of those genes do not appear in the mouse genotype(s).

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Pitx3^ak/Pitx3^ak

        involves: 129S1/Sv * C57BL/6 * C57BLKS/J

• nervous system phenotype
• abnormal dorsal striatum morphology (MGI Ref ID J:109319)
  • results using the key dopamine neuronal marker, TH, suggest a reduction of neurons in the dorsal striatum, however, not in the nucleus accumbens or olfactory tubercle implying a defective nigrostriatal pathway
• abnormal substantia nigra morphology (MGI Ref ID J:109319)
  • Nissl staining indicates that cell density is dramatically reduced in the substantia nigra pas as compared to wild-type
  • dopaminergic neurons remaining in the substantia nigra appear atrophic with somewhat shrunken cell bodies
  • results using both the key dopamine neuronal marker, TH, and Fluorogold retrograde labeling suggest the absence of dopaminergic neurons in the substantia nigra pas compacta indicating that nigrostriatal projections do not develop
  • neuron loss is apparent in newborn mice
• decreased dopamine level (MGI Ref ID J:109319)
  • levels are reduced to 10% of wildtype in the dorsal striatum, however levels in the ventral striatum are not affected
• loss of dopaminergic neurons (MGI Ref ID J:109319)
  • selective loss of A9 dopaminergic neurons in the substantia nigra; A10 neurons in the ventral tegmental area appear to be intact
• behavior/neurological phenotype
• abnormal locomotor activity (MGI Ref ID J:98209)
  • higher ambulatory activity than control during lights-on period, however, lower ambulatory activity than control during lights-off period
• decreased vertical activity (MGI Ref ID J:98209)
  • mice exhibit a decrease in rearing and hindlimb stepping as measured in the transparent cylinder, however, administration of L-DOPA increases spontaneous activity to the same or higher than wildtype
• hyperactivity (MGI Ref ID J:98209)
  • total horizontal movements during a 22 hour period are slightly increased over that of control
• impaired coordination (MGI Ref ID J:98209)
  • mice exhibit longer times to traverse a balance beam challenge and a 25% increase in the number of steps as compared to controls, however, administration of L-DOPA reduced beam time and step number almost to wild-type levels
  • in a vertical pole test, mice take longer than controls to orient downwards; L-DOPA administration reduces orientation time

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Pitx3^ak/Pitx3^ak

        either: (involves: 129/Sv * C57BLKS) or (involves: 129/Sv * C57BL/6)

• pigmentation phenotype
• abnormal iris pigmentation (MGI Ref ID J:5084)
  • intensly pigmented around the pupil at E13
  • pupillary area replaced by iris at E17-18
• behavior/neurological phenotype
• hypoactivity (MGI Ref ID J:82907)
  • reduced spontaneous activity at night
• endocrine/exocrine gland phenotype
• abnormal lacrimal gland morphology (MGI Ref ID J:5084)
  • enlarged lacrimal gland partially fills the orbit
• growth/size phenotype
• decreased body size (MGI Ref ID J:5084)
  • slightly smaller than normal
• reproductive system phenotype
• reduced fertility (MGI Ref ID J:5084)
  • fertility is reduced at generation F3 and beyond, particularly for females
• vision/eye phenotype
• abnormal anterior eye segment morphology (MGI Ref ID J:5084)
• abnormal iris pigmentation (MGI Ref ID J:5084)
  • intensly pigmented around the pupil at E13
  • pupillary area replaced by iris at E17-18
• abnormal lens development (MGI Ref ID J:5084)
  • little growth or organization of the lens vesicle after E11
• abnormal pupil morphology (MGI Ref ID J:5084)
  • no pupil at birth
• abnormal eye distance/ position (MGI Ref ID J:5084)
  • ocular area slightly concave after eyes open
• abnormal lacrimal gland morphology (MGI Ref ID J:5084)
  • enlarged lacrimal gland partially fills the orbit
• abnormal posterior eye segment morphology (MGI Ref ID J:5084)
• abnormal ocular fundus morphology (MGI Ref ID J:5084)
  • abnormal growth of the eyecup after E13
  • sensory and pigmented layers remain separated
• abnormal retina morphology (MGI Ref ID J:5084)
  • many retinal folds at birth
  • partially fills the vitreous chamber
• microphthalmia (MGI Ref ID J:5084)
  • eyes slightly smaller than normal at birth
  • slightly smaller and uneven at E13
• nervous system phenotype
• abnormal midbrain morphology (MGI Ref ID J:82746)
  • less cellularity in the substantia nigra
  • tyrosine hydroxylase immunoreactivity absent in the substantia nigra
  • decreased numbers of nigrostriatal fibers
  • at E12.5, mesencephalon dopaminergic neurons are normal
  • by the first day after birth there is a 91% reduction in neurons with tyrosine hydroxylase immunoreactivity
  • reduced activity in the ventral tegmental area but slower to develop
  • dorsal tier of the pars compacta of the substantia nigra retains tyrosine hydroxylase activity

View Research Applications

Research Applications

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

Pitx3^ak related

Neurobiology Research
Parkinson's Disease

Sensorineural Research
Cataracts (cortical)

Genes & Alleles

Gene & Allele Information

Allele Symbol		Pitx3ak
Allele Name		aphakia
Allele Type		Spontaneous
Common Name(s)		ak;
Strain of Origin		129S1/Sv-Kitl
Gene Symbol and Name		Pitx3, paired-like homeodomain transcription factor 3
Chromosome		19
Gene Common Name(s)		CTPP4; MGC12766; PTX3; ak; aphakia;
Molecular Note		This allele carries a 652 bp deletion in the promoter region of the gene, located 2.5 kb upstream of the transcription start site. The deletion cosegregated with the ak mutation. In situ hybridization studies of homozygous mutant mice did not detect transcripts in the lens placode or at later developmental stages of the lens. [MGI Ref ID J:63167] [MGI Ref ID J:68175]

Genotyping

Genotyping Information

This strain will not have a genotyping protocol or one is not currently available.

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Varnum DS; Stevens LC. 1968. Aphakia, a new mutation in the mouse. J Hered 59(2):147-50. [PubMed: 4970465]  [MGI Ref ID J:5084]

Additional References

Smidt MP; Smits SM; Bouwmeester H; Hamers FP; van der Linden AJ; Hellemons AJ; Graw J; Burbach JP. 2004. Early developmental failure of substantia nigra dopamine neurons in mice lacking the homeodomain gene Pitx3. Development 131(5):1145-55. [PubMed: 14973278]  [MGI Ref ID J:88592]

Pitx3^ak related

Ardayfio P; Moon J; Leung KK; Youn-Hwang D; Kim KS. 2008. Impaired learning and memory in Pitx3 deficient aphakia mice: A genetic model for striatum-dependent cognitive symptoms in Parkinson's disease. Neurobiol Dis :. [PubMed: 18573342]  [MGI Ref ID J:136304]

Coulon V; L'Honore A; Ouimette JF; Dumontier E; van den Munckhof P; Drouin J. 2007. A muscle-specific promoter directs Pitx3 gene expression in skeletal muscle cells. J Biol Chem 282(45):33192-200. [PubMed: 17848564]  [MGI Ref ID J:126948]

Ding Y; Restrepo J; Won L; Hwang DY; Kim KS; Kang UJ. 2007. Chronic 3,4-dihydroxyphenylalanine treatment induces dyskinesia in aphakia mice, a novel genetic model of Parkinson's disease. Neurobiol Dis 27(1):11-23. [PubMed: 17499513]  [MGI Ref ID J:122000]

Grimm C; Chatterjee B; Favor J; Immervoll T; Loster J; Klopp N; Sandulache R; Graw J. 1998. Aphakia (ak), a mouse mutation affecting early eye development: fine mapping, consideration of candidate genes and altered Pax6 and Six3 gene expression pattern. Dev Genet 23(4):299-316. [PubMed: 9883582]  [MGI Ref ID J:51693]

Hwang DY; Ardayfio P; Kang UJ; Semina EV; Kim KS. 2003. Selective loss of dopaminergic neurons in the substantia nigra of Pitx3-deficient aphakia mice. Brain Res Mol Brain Res 114(2):123-31. [PubMed: 12829322]  [MGI Ref ID J:109319]

Hwang DY; Fleming SM; Ardayfio P; Moran-Gates T; Kim H; Tarazi FI; Chesselet MF; Kim KS. 2005. 3,4-dihydroxyphenylalanine reverses the motor deficits in Pitx3-deficient aphakia mice: behavioral characterization of a novel genetic model of Parkinson's disease. J Neurosci 25(8):2132-7. [PubMed: 15728853]  [MGI Ref ID J:98209]

Jacobs FM; Smits SM; Noorlander CW; von Oerthel L; van der Linden AJ; Burbach JP; Smidt MP. 2007. Retinoic acid counteracts developmental defects in the substantia nigra caused by Pitx3 deficiency. Development 134(14):2673-84. [PubMed: 17592014]  [MGI Ref ID J:122792]

Kas MJ; van der Linden AJ; Oppelaar H; von Oerthel L; Ramakers GM; Smidt MP. 2008. Phenotypic segregation of aphakia and Pitx3-null mutants reveals that Pitx3 deficiency increases consolidation of specific movement components Behav Brain Res 186(2):208-14. [PubMed: 17919745]  [MGI Ref ID J:125552]

Kim J; Inoue K; Ishii J; Vanti WB; Voronov SV; Murchison E; Hannon G; Abeliovich A. 2007. A MicroRNA feedback circuit in midbrain dopamine neurons. Science 317(5842):1220-4. [PubMed: 17761882]  [MGI Ref ID J:125222]

Nunes I; Tovmasian LT; Silva RM; Burke RE; Goff SP. 2003. Pitx3 is required for development of substantia nigra dopaminergic neurons. Proc Natl Acad Sci U S A 100(7):4245-50. [PubMed: 12655058]  [MGI Ref ID J:82746]

Rieger DK; Reichenberger E; McLean W; Sidow A; Olsen BR. 2001. A double-deletion mutation in the pitx3 gene causes arrested lens development in aphakia mice. Genomics 72(1):61-72. [PubMed: 11247667]  [MGI Ref ID J:68175]

Semina EV; Murray JC; Reiter R; Hrstka RF; Graw J. 2000. Deletion in the promoter region and altered expression of pitx3 homeobox gene in aphakia mice Hum Mol Genet 9(11):1575-85. [PubMed: 10861284]  [MGI Ref ID J:63167]

Singh B; Wilson JH; Vasavada HH; Guo Z; Allore HG; Zeiss CJ. 2007. Motor deficits and altered striatal gene expression in aphakia (ak) mice. Brain Res 1185:283-92. [PubMed: 17949697]  [MGI Ref ID J:128707]

Smits SM; Mathon DS; Burbach JP; Ramakers GM; Smidt MP. 2005. Molecular and cellular alterations in the Pitx3-deficient midbrain dopaminergic system. Mol Cell Neurosci 30(3):352-63. [PubMed: 16140547]  [MGI Ref ID J:102233]

Smits SM; van der Nobelen S; Hornman KJ; von Oerthel L; Burbach JP; Smidt MP. 2005. Signalling through phospholipase C beta 4 is not essential for midbrain dopaminergic neuron survival. Neuroscience 136(1):171-9. [PubMed: 16198487]  [MGI Ref ID J:104551]

Varnum DS; Stevens LC. 1975. Aphakia linked with brachymorphic. Mouse News Lett 53:35.  [MGI Ref ID J:13685]

Webster EH Jr; Zwaan J; Cooper P. 1986. Abnormal accumulation of sulphated materials in lens tissue of mice with the aphakia mutation. J Embryol Exp Morphol 92:85-101. [PubMed: 3522797]  [MGI Ref ID J:8330]

Zwaan J. 1975. Immunofluorescent studies on aphakia, a mutation of a gene involved in the control of lens differentiation in the mouse embryo. Dev Biol 44(2):306-12. [PubMed: 1093912]  [MGI Ref ID J:5541]

Zwaan J; Kirkland BM. 1975. Malorientation of mitotic figures in the early lens rudiment of aphakia mouse embryos. Anat Rec 182(3):345-54. [PubMed: 1155804]  [MGI Ref ID J:5562]

Zwaan J; Webster EH Jr. 1984. Histochemical analysis of extracellular matrix material during embryonic mouse lens morphogenesis in an aphakic strain of mice. Dev Biol 104(2):380-9. [PubMed: 6745489]  [MGI Ref ID J:7505]

de Rover M; Lodder JC; Smidt MP; Brussaard AB. 2006. Pitx3 deficiency in mice affects cholinergic modulation of GABAergic synapses in the nucleus accumbens. J Neurophysiol 96(4):2034-41. [PubMed: 16837663]  [MGI Ref ID J:135703]

van den Munckhof P; Gilbert F; Chamberland M; Levesque D; Drouin J. 2006. Striatal neuroadaptation and rescue of locomotor deficit by L-dopa in aphakia mice, a model of Parkinson's disease. J Neurochem 96(1):160-70. [PubMed: 16269007]  [MGI Ref ID J:104915]

van den Munckhof P; Luk KC; Ste-Marie L; Montgomery J; Blanchet PJ; Sadikot AF; Drouin J. 2003. Pitx3 is required for motor activity and for survival of a subset of midbrain dopaminergic neurons. Development 130(11):2535-42. [PubMed: 12702666]  [MGI Ref ID J:82907]

Health & husbandry

Health & Colony Maintenance Information

Currently there no information available for this strain. This may be due to the supply level of this strain.

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information.

Supply Notes

Cryorecovery - Standard. At least two mice that carry the mutation (if it is a mutant strain) will be provided. The total number of animals provided, their gender and genotype will vary. Please inquire if larger numbers of animals with specific genotypes and genders are needed. IMPORTANT NOTE: The genotypes of the animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire for possible genotypes for this specific strain. Animals typically ship within 13 to 16 weeks from your order. If a second cryorecovery is needed in order to provide the minimum number of animals, animals will typically ship within 25 weeks. Cryorecovery to establish a Dedicated Supply for greater quantities of mice. One to two pairs will be recovered to establish a Dedicated Supply of mice. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 or 1-207-288-5845. This strain is included in the Mouse Mutant Resource collection. Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	Heterozygote from the colony
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

General Terms and Conditions

See Terms of Use

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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Ordering and Purchasing Information

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Contact Information
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Tel: 800.422.6423 or 207.288.5845
Fax: 207.288.6150
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Terms of Use

Terms of Use

General Terms and Conditions

Contact information

General inquiries

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phone:	207-288-6470
fax:	207-288-6655

JAX^® Mice & Services Conditions of Use

“Each recipient institution, including its employees and other researchers under its control (RECIPIENT), of mice or services using mice from The Jackson Laboratory (TJL) agrees that such mice, descendants of those mice derived by inbreeding or crossbreeding, including unmodified derivatives of those mice or their descendants (“MICE”) shall not be: (i) used for any purpose other than the internal research of the RECIPIENT, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services with respect to MICE. Acceptance of MICE from TJL shall be deemed agreement by RECIPIENT to these conditions, and departure from these conditions requires The Jackson Laboratory’s prior written authorization.”

In case of dissatisfaction for a valid reason and claimed in writing by a purchaser within ninety (90) days of receipt of MICE, products or services, The Jackson Laboratory will, at its option, provide credit or replacement for the MICE or product received or the services provided.

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MICE and biological materials are to be used in a safe manner and in accordance with all applicable governmental rules and regulations.

The foregoing represents the General Terms and Conditions applicable to The Jackson Laboratory’s MICE, products and services. In addition, special terms and conditions of sale of certain MICE, products and services may be set forth separately in The Jackson Laboratory web pages, catalogs, price lists, contracts, and/or other documents, and these special terms and conditions shall also govern the sale of these MICE, products and services by The Jackson Laboratory, and by its licensees and distributors.

Acceptance of delivery of MICE, products or services shall be deemed agreement to these terms and conditions. No purchase order or other document transmitted by purchaser or recipient that may modify the terms and conditions hereof, shall be in any way binding on The Jackson Laboratory, and instead the terms and conditions set forth herein, including any special terms and conditions set forth separately, shall govern the sale of MICE, products services by The Jackson Laboratory.