Description

Strain Information

Type Mutant Stock; Mating System Heterozygote x Homozygote         (Female x Male) Mating System Heterozygote x Heterozygote         (Female x Male) Species laboratory mouse Generation F8+60 (07-DEC-07)

Appearance
agouti
Related Genotype: A/A

Description
Mice homozygous for the forebrain overgrowth recessive spontaneous mutation (fog) display forebrain, lumbo-sacral, and facial defects most likely due to excessive growth or cellular proliferation ultimately causing abnormalities in neural tube closure. The phenotypes manifest as head bumps and sacral spina bifida and individual mice can have either or both. Three unique features of the mutant are (1) the growth of telencephalon cells into the surrounding mesenchyme, (2) presence of an encephalocele through the midline cleft in some mutants, and (3) dissociation of the tail defect from the caudal neural tube defect. The fog mutation maps to mouse Chromosome 10 near D10Mit262 and D10Mit230.

Control Information

Allele	Control
Apaf1fog	Heterozygote from the colony
Apaf1fog	Untyped from the colony
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Apaf1

004373

B6;129S6-Apaf1tm1Her/J

View Strains carrying other alleles of Apaf1     (1 strain)

Phenotype

Phenotype Information

Mammalian Phenotype Terms assigned by genotype

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

Apaf1^fog/Apaf1⁺

        involves: C3H/HeJ

• normal phenotype
• no abnormal phenotype detected (MGI Ref ID J:41353)
  • no details provided; most heterozygotes are viable and fertilie

Apaf1^fog/Apaf1^fog

        involves: C3H/HeJ

• cardiovascular system phenotype
• intracerebral hemorrhage (MGI Ref ID J:41353)
  • in some foci of proliferation, rupture of blood vessels occurs, causing hemorrhages into parenchyma of cerebral hemispheres
  • by E17.5, massive hemorrhage in brain and subectodermal tissue of the frontal bulges can be seen through the skin
• craniofacial phenotype
• abnormal head morphology (MGI Ref ID J:41353)
  • affected animals exhibit usually bilateral bumps over the forehead; bumps may be larger on one side or give the appearance of a wholly enlarged forehead
  • in adult mice, bumps usually contain loose connective tissue
• midline facial cleft (MGI Ref ID J:41353)
  • a few embryos exhibit facial clefting at E12 and later; mutant embryos observed at E16.5-17.5 display herniation of entire forebrain through middle of face
• short snout (MGI Ref ID J:41353)
  • affected animals may show shorter snouts
• abnormal skull morphology (MGI Ref ID J:41353)
  • in mutant embryos with facial clefts observed at E16.5-17.5, skulls are flat due to absence of cephalic flexure in rostrally extended brain
• abnormal calvaria morphology (MGI Ref ID J:41353)
  • show normal sutures, but one to three round holes up to 3 mm in diameter) mark sites where ossification had been impaired by enlarged forebrain
• lethality-postnatal
• postnatal lethality (MGI Ref ID J:41353)
  • severity of defects results in death shortly after birth; preweaning lethality is 6%
• lethality-prenatal/perinatal
• perinatal lethality (MGI Ref ID J:41353)
  • severity of defects results in death at or shortly after birth
• life span-post-weaning/aging
• decreased survivor rate (MGI Ref ID J:41353)
  • some mice, including animals with combinations of most or all defects do survive to adulthood and reproduce
• limbs/digits/tail phenotype
• curly tail (MGI Ref ID J:41353)
  • around 50% of mutants may display curly or looped tails, shaped like a corkscrew; may be present singly (20%) or in combination with exencephaly and/or spina bifida (40%)
• kinked tail (MGI Ref ID J:41353)
  • tails are malformed in about half of the mutants; tails may show distal kinks
• nervous system phenotype
• *normal* nervous system phenotype (MGI Ref ID J:131954)
  • in adult animals, neuronal counts of spinal and cranial motoneurons, spinal interneurons, dorsal root ganglion sensory neurons, and superior cervical ganglion sympathetic neurons are not different from wild-type
• abnormal embryonic neuroepithelium morphology (MGI Ref ID J:41353)
  • some cell death is observed in lesions of telencephalic walls at E10.5
  • cells are less densely packed and protrude slightly into lumen of lateral ventricle
• abnormal forebrain morphology (MGI Ref ID J:41353)
  • at E13.5-14.5, mass of forebrain tissue has increased due to hemorrhage and multifocal proliferation such that cerebral hemispheres are starting to bulge from surface of head; by E17.5, forebrain tissue mass compressed overlying subepidermal mesenchyme
  • in embryos (E17.5), herniation of forebrain tissue may be observed; forebrain is enlarged
• abnormal telencephalon morphology (MGI Ref ID J:41353)
  • at E10.5, telencephalic walls are folded in embryos with open cranial neuropore
  • lesions of telencephalic walls are detected at E10.5
  • cells of walls extrude outwardly, compressing connective tissue of meninges and subepidermal mesenchyme which will form calvaria; such extrusions are observed extending into mesenchyme around basal forebrain and sometimes penetrate wall of the pharynx
• abnormal cerebrum morphology (MGI Ref ID J:41353)
  • at E13.5 and E14.5, cerebral hemispheres show many folds and intraparenchymal proliferation foci
  • mesenchymal and epidermal cover of hemispheres is extremely thin on top
• abnormal lateral ventricle morphology (MGI Ref ID J:41353)
  • at E10.5, embryos with open cranial neuropore display collapsed lateral ventricles
  • cells of telencephalic walls are less densely packed than in wild-type and protrude slightly into lumen of lateral ventricle at E10.5; at E12.5, protrusions are more conspicuous with more cells and vascularization
  • lumen of ventricles are narrower than wild-type at E12.5; ventricles often contain blood
• delayed neural tube closure (MGI Ref ID J:41353)
  • at E10.5, cranial neuropore is still open whereas it is closed in wild-type embryos; closure in essentially all mutants is observed at E12.5
• exencephaly (MGI Ref ID J:41353)
  • mutants show exencephaly or herniation of the forebrain; may be present singly or in combination with tail defects and/or spina bifida
  • forebrain exencephaly is observed, similar to other Apaf1-null mutants
  • in adult homozygotes, exencephalic forebrain is covered by skin and hair an appears as forehead bumps
• intracerebral hemorrhage (MGI Ref ID J:41353)
  • in some foci of proliferation, rupture of blood vessels occurs, causing hemorrhages into parenchyma of cerebral hemispheres
  • by E17.5, massive hemorrhage in brain and subectodermal tissue of the frontal bulges can be seen through the skin
• spina bifida (MGI Ref ID J:131954)
  • animals also display mild-to-moderate lumbar spina bifida
• spina bifida occulta (MGI Ref ID J:41353)
  • spina bifida is observed in some pups, sometimes as an opening in the lumbar region, or healed but still visible as a small scar; may be present singly (40%) or in combination with exencephaly and/or tail defects (20%)
  • persistent caudal neuropore occurs separately from tail deflections in 60% of affected animals
  • lumbo-sacral neural tube defects observed in about half the animals are secondarily closed during late gestation and remain visible as small wound on dorsal aspect of sacral region in newborns
• reproductive system phenotype
• reduced female fertility (MGI Ref ID J:41353)
  • some adult females breed poorly or do not reproduce
• reduced male fertility (MGI Ref ID J:41353)
  • some adult males breed poorly or do not reproduce
• skeleton phenotype
• abnormal skull morphology (MGI Ref ID J:41353)
  • in mutant embryos with facial clefts observed at E16.5-17.5, skulls are flat due to absence of cephalic flexure in rostrally extended brain
• abnormal calvaria morphology (MGI Ref ID J:41353)
  • show normal sutures, but one to three round holes up to 3 mm in diameter) mark sites where ossification had been impaired by enlarged forebrain

Research Applications

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

Apaf1^fog related

Apoptosis Research

Cell Biology Research
Signal Transduction

Developmental Biology Research
Neural Tube Defects
Neurodevelopmental Defects

Neurobiology Research
Neural Tube Defects
Neurodevelopmental Defects

Reproductive Biology Research
Fertility Defects

Genes & Alleles

Gene & Allele Information

Allele Symbol		Apaf1fog
Allele Name		forebrain overgrowth
Common Name(s)		fog;
Strain of Origin		STOCK dwg/J
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;
General Note		Mutant mice are characterized by forebrain overgrowth and excessive cellular proliferation in the midline cleft. Human APAF1 is a candidate gene for Noonan Syndrome (OMIM 163950), a complex disease with some patients showing facial, cardiac, retinal, andlimb abnormalities reminiscent of defective apoptosis (J:49840).
Molecular Note		Defective mRNA processing appears to be the cause of the markedly reduced normal mRNA levels, protein levels, and activity in fog mutant mice. Complementation testing confirmed that the fog mutant mouse is an allele of Apaf1. [MGI Ref ID J:71086]

Genotyping

Genotyping Information

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

Helpful Links

Optimizing PCR Protocols

References

References

Additional References

Harris BS; Franz T; Ullrich S; Cook S; Bronson RT; Davisson MT. 1997. Forebrain overgrowth (fog): a new mutation in the mouse affecting neural tube development. Teratology 55(4):231-40. [PubMed: 9216040]  [MGI Ref ID J:41353]

Apaf1^fog related

Harris BS; Franz T; Ullrich S; Cook S; Bronson RT; Davisson MT. 1997. Forebrain overgrowth (fog): a new mutation in the mouse affecting neural tube development. Teratology 55(4):231-40. [PubMed: 9216040]  [MGI Ref ID J:41353]

Hisatomi T; Nakazawa T; Noda K; Almulki L; Miyahara S; Nakao S; Ito Y; She H; Kohno R; Michaud N; Ishibashi T; Hafezi-Moghadam A; Badley AD; Kroemer G; Miller JW. 2008. HIV protease inhibitors provide neuroprotection through inhibition of mitochondrial apoptosis in mice. J Clin Invest 118(6):2025-38. [PubMed: 18497877]  [MGI Ref ID J:137728]

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]

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]

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]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           A1

Purchasing information

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

Pricing

Control Information

Allele	Control
Apaf1fog	Heterozygote from the colony
Apaf1fog	Untyped 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

View JAX^® Mice & Services Conditions 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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