Description

Strain Information

Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse Generation ?+F1pN1 (14-MAR-04)   Donating Investigator Joachim Herz,   Univ of Texas Southwest Med Ctr Dallas

Description
Mice that are heterozygous for the targeted allele are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. Most homozygous mutant mice have a perinatal lethal phenotype with severe neuropathology (exencephaly or cranioschesis). Five percent of homozygous null mice survive to weaning age with hydrocephalus, but do not survive much longer. Another five percent survive to adulthood and exhibit hyperactivity. Surviving male homozygotes are infertile. Homozygous female mice are fertile and have litters, but at a reduced frequency. Homozygous male mice are infertile due to massive degeneration of spermatogonia and reduced sperm. At age E9.5 in development neural tube closure defects and thickened neuropithelium appear. No targeted gene product (protein) was immunodetected in homozygous mutant mice. Fibroblast extracts from mutant adult mice do not activate caspase-3. This mutant mouse strain represents a model that may be useful in studies of the role of apoptotic cell death in disease processes.

Development
A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes was used to disrupt the targeted gene with an arginine-to-glycine mutation at amino acid 111 and a stop codon inserted at amino acid 124. The construct was electroporated into 129S6/SvEv derived SM-1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts.

Control Information

	Control
	Wild-type from the colony
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Apaf1

002979

STOCK Apaf1fog/J

View Strains carrying other alleles of Apaf1     (1 strain)

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

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

Apaf1^tm1Her/Apaf1^tm1Her

        involves: 129S6/SvEvTac * C57BL/6J

• behavior/neurological phenotype
• hyperactivity (MGI Ref ID J:60409)
  • at 10 weeks, surviving homozygotes are strikingly hyperactive, travelling longer distances and spending more time moving than sex-matched wild-type or heterozygous mice in the open-field test
  • the distance traveled over an one-hour period is on average 10x greater than that covered by wild-type or heterozygous mice
• craniofacial phenotype
• abnormal palate morphology (MGI Ref ID J:60409)
  • at E15.5, homozygotes display prominent palate defects
• abnormal viscerocranium morphology (MGI Ref ID J:60409)
• cranioschisis (MGI Ref ID J:60409)
  • homozygotes commonly exhibit cranioschisis
• lethality-prenatal/perinatal
• perinatal lethality (MGI Ref ID J:60409)
  • most homozygotes die perinatally
  • only 5% of homozygotes survive to adulthood (at least 10 months), in the absence of developmental defects in kidney, lung, heart, liver or brain (at the level of hippocampus, thalamus/basal ganglia, and cerebellum)
• life span-post-weaning/aging
• premature death (MGI Ref ID J:60409)
  • 3 of 14 homozygotes surviving postnatally die at 8 weeks due to complications from hydrocephalus; the remainig homozygotes survive through 10 months of age
• nervous system phenotype
• abnormal brain ventricle morphology (MGI Ref ID J:60409)
  • at E12.5, the ventricles in the developing mutant brain are compressed, as a result of supernumerary cells in the periventricular zone
• abnormal lateral ventricle morphology (MGI Ref ID J:60409)
  • by E13.5, the increased number of cells in the periventricular zone have invaded and obliterated the lateral ventricles, and the ganglionic eminence is almost undetectable
• abnormal embryonic neuroepithelium morphology (MGI Ref ID J:60409)
  • homozygotes exhibit abnormal thickening of the neuroepithelium as early as E9.5
• abnormal embryonic/fetal subventricular zone morphology (MGI Ref ID J:60409)
  • by E13.5, the increased number of cells in the periventricular zone have invaded and obliterated the lateral ventricles, and the ganglionic eminence is almost undetectable
• abnormal neurogenesis (MGI Ref ID J:60409)
  • at E13.5, homozygotes exhibit ectopic regions of neurogenesis, with supernumerary developing neurons abnormally distributed in the subventricular zone
• abnormal neuronal migration (MGI Ref ID J:60409)
  • mature neurons developing in ectopic regions fail to migrate to their proper position in the cortex
• decreased neuron apoptosis (MGI Ref ID J:60409)
• exencephaly (MGI Ref ID J:60409)
  • homozygotes commonly exhibit exencephaly
• hydroencephaly (MGI Ref ID J:60409)
• open neural tube (MGI Ref ID J:60409)
  • at E9.5, homozygotes frequently fail to close the neural tube
• reproductive system phenotype
• abnormal seminiferous tubule morphology (MGI Ref ID J:60409)
  • adult male homozygotes invariably exhibit patent seminiferous tubules
• abnormal spermatogonia morphology (MGI Ref ID J:60409)
  • at 2 to 10 months, surviving male homozygotes exhibit massive degeneration of spermatogonia in the testis
• azoospermia (MGI Ref ID J:60409)
  • at 2 to 10 months of age, the epidydimis of male homozygotes contains cellular debris and is devoid of viable, mature sperm; however, both Sertoli and Leydig cells are present, and normal secondary sexual features are preserved
• male infertility (MGI Ref ID J:60409)
  • adult male homozygotes are infertile
• reduced female fertility (MGI Ref ID J:60409)
  • adult female homozygotes are fertile and breed successfully, albeit at a reduced rate
  • mutant ovaries show normal follicular development and function and lack atretic follicles
• respiratory system phenotype
• abnormal nasal septum morphology (MGI Ref ID J:60409)
  • at E13.5, homozygotes exhibit nasal septal defects
• skeleton phenotype
• abnormal viscerocranium morphology (MGI Ref ID J:60409)
• cranioschisis (MGI Ref ID J:60409)
  • homozygotes commonly exhibit cranioschisis
• tumorigenesis
• *normal* tumorigenesis (MGI Ref ID J:60409)
  • surviving homozygotes do NOT exhibit spontaneous soft tissue tumor formation
• vision/eye phenotype
• abnormal retinal neuronal layer morphology (MGI Ref ID J:60409)
  • at E15.5, homozygotes exhibit retinal thickening
• endocrine/exocrine gland phenotype
• abnormal seminiferous tubule morphology (MGI Ref ID J:60409)
  • adult male homozygotes invariably exhibit patent seminiferous tubules
• cellular phenotype
• abnormal apoptosis (MGI Ref ID J:60409)
  • cell extracts prepared from mutant MEFs fail to activate procaspase-3 in the presence of dATP
  • in response to staurosporine-induced apoptosis, mutant MEFs exhibit the expected morphological features of cell death, but fail to activate caspase-3 or -9
• hearing/vestibular/ear phenotype
• abnormal otic vesicle formation (MGI Ref ID J:60409)
  • at E9.5, the neuroepithelium lining the otic vesicles is thickened and poorly organized
• digestive/alimentary phenotype
• abnormal palate morphology (MGI Ref ID J:60409)
  • at E15.5, homozygotes display prominent palate defects

View Research Applications

Research Applications

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

Apaf1^tm1Her related

Developmental Biology Research
Neural Tube Defects

Neurobiology Research
Neural Tube Defects

Genes & Alleles

Gene & Allele Information

Allele Symbol		Apaf1tm1Her
Allele Name		targeted mutation 1, Joachim Herz
Allele Type		Targeted (knock-out)
Common Name(s)		Apaf1-;
Mutation Made By		Narimon Honarpour,   Univ of Texas Southwestern Medical Ctr
Strain of Origin		129S6/SvEvTac
ES Cell Line Name		SM1
ES Cell Line Strain		129S6/SvEvTac
Gene Symbol and Name		Apaf1, apoptotic peptidase activating factor 1
Chromosome		10
Gene Common Name(s)		6230400I06Rik; Apaf1l; CED4; DKFZp781B1145; RIKEN cDNA 6230400I06 gene; apoptotic protease activating factor 1 like; fog; forebrain overgrowth;
Molecular Note		Insertion of a neomycin casette into sequences encoding the Ced 4 homology domain corresponding to amino acid 111. Insertion disrupts the reading frame of the protein. [MGI Ref ID J:60409]

Genotyping

Genotyping Information

Genotyping Protocols

Apaf1^tm1Her, STD PCR, vers. 2
NEOTD (Generic Neo), STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Honarpour N; Du C; Richardson JA; Hammer RE; Wang X; Herz J. 2000. Adult Apaf-1-deficient mice exhibit male infertility. Dev Biol 218(2):248-58. [PubMed: 10656767]  [MGI Ref ID J:60409]

Additional References

Honarpour N; Tabuchi K; Stark JM; Hammer RE; Sudhof TC; Parada LF; Wang X; Richardson JA; Herz J. 2001. Embryonic neuronal death due to neurotrophin and neurotransmitter deprivation occurs independent of Apaf-1. Neuroscience 106(2):263-74. [PubMed: 11566499]  [MGI Ref ID J:85905]

Apaf1^tm1Her related

Aiyer AR; Honarpour N; Herz J; Srivastava D. 2005. Loss of Apaf-1 leads to partial rescue of the HAND2-null phenotype. Dev Biol 278(1):155-62. [PubMed: 15649468]  [MGI Ref ID J:96490]

Hao Z; Duncan GS; Chang CC; Elia A; Fang M; Wakeham A; Okada H; Calzascia T; Jang Y; You-Ten A; Yeh WC; Ohashi P; Wang X; Mak TW. 2005. Specific ablation of the apoptotic functions of cytochrome C reveals a differential requirement for cytochrome C and Apaf-1 in apoptosis. Cell 121(4):579-91. [PubMed: 15907471]  [MGI Ref ID J:98949]

Honarpour N; Gilbert SL; Lahn BT; Wang X; Herz J. 2001. Apaf-1 deficiency and neural tube closure defects are found in fog mice. Proc Natl Acad Sci U S A 98(17):9683-7. [PubMed: 11504943]  [MGI Ref ID J:71086]

Honarpour N; Tabuchi K; Stark JM; Hammer RE; Sudhof TC; Parada LF; Wang X; Richardson JA; Herz J. 2001. Embryonic neuronal death due to neurotrophin and neurotransmitter deprivation occurs independent of Apaf-1. Neuroscience 106(2):263-74. [PubMed: 11566499]  [MGI Ref ID J:85905]

Oppenheim RW; Blomgren K; Ethell DW; Koike M; Komatsu M; Prevette D; Roth KA; Uchiyama Y; Vinsant S; Zhu C. 2008. Developing postmitotic mammalian neurons in vivo lacking Apaf-1 undergo programmed cell death by a caspase-independent, nonapoptotic pathway involving autophagy. J Neurosci 28(6):1490-7. [PubMed: 18256270]  [MGI Ref ID J:131954]

Smith MI; Deshmukh M. 2007. Endoplasmic reticulum stress-induced apoptosis requires bax for commitment and Apaf-1 for execution in primary neurons. Cell Death Differ 14(5):1011-9. [PubMed: 17218955]  [MGI Ref ID J:139276]

Steckley D; Karajgikar M; Dale LB; Fuerth B; Swan P; Drummond-Main C; Poulter MO; Ferguson SS; Strasser A; Cregan SP. 2007. Puma is a dominant regulator of oxidative stress induced Bax activation and neuronal apoptosis. J Neurosci 27(47):12989-99. [PubMed: 18032672]  [MGI Ref ID J:127640]

Vaughn AE; Deshmukh M. 2007. Essential postmitochondrial function of p53 uncovered in DNA damage-induced apoptosis in neurons. Cell Death Differ 14(5):973-81. [PubMed: 17218959]  [MGI Ref ID J:139242]

Wright KM; Vaughn AE; Deshmukh M. 2007. Apoptosome dependent caspase-3 activation pathway is non-redundant and necessary for apoptosis in sympathetic neurons. Cell Death Differ 14(3):625-33. [PubMed: 16932756]  [MGI Ref ID J:132340]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Breeding & Husbandry	The resulting chimeric animals were crossed to C57BL/6 female mice. The strain is maintained by heterozygous intercrossing. Expected coat color is: Agouti and Black.
Diet Information	LabDiet® 5K52/5K67

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. The recovery process begins when a signed agreement form is returned to the Customer Service Department after order placement. Although results vary by strain, at least two males and two females (two pairs) will be provided, typically within 15 weeks of our receipt of the signed agreement form. If the first recovery attempt is unsuccessful or only one pair is recovered, a second recovery will be done, extending the delivery time to approximately 25 weeks. At least one member of each pair will be of known genotype and will carry the mutation if it is a mutant strain. Please note that pairs may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation of the strain. Mating schemes are sometimes modified for successful cryopreservation. Price represents a repository maintenance fee, which includes the cost of recovery of the strain from the cryopreservation resource and the periodic replacement of the frozen embryos used for recovery. 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 Induced Mutant Resource Colony collection.

Control Information

	Control
	Wild-type 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
Orders & Technical Support
Tel: 800.422.6423 or 207.288.5845
Fax: 207.288.6150
Technical Support Email Form

Terms of Use

Terms of Use

General Terms and Conditions

Contact information

General inquiries

Contracts Administration

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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