Mice homozygous for the splotch spontaneous mutation (Pax3^Sp) die at E13 due to neural tube defects. Malformations of homozygous mutant embryos include rachischisis in the lumbosacral region and frequently in the region of the hindbrain. Heterozygous splotch mice show white spotting on the belly and occasionally on the back, feet, and tail. Splotch is a point mutation within intron 3 of the paired homeobox 3 (Pax3) gene on mouse Chromosome 1. The mutation interferes with normal splicing of intron 3 and leads to at least 4 aberrantly spliced mRNAs with exon 4 deleted. The Pax3^Sp mutation also impairs homodimerization of the protein, a function associated with the octapeptide-encoding central segment of the gene. There are multiple alleles at this locus including splotch-delayed (Pax3^Sp-d, Stock No. 000565), which is similar to splotch but displays caudal rachischisis only.

Genetics

Pax3^Sp

Allele Symbol: Pax3^Sp

Allele Name	splotch
Allele Type	Spontaneous
Allele Synonym(s)	Sp
Gene Symbol and Name	Pax3, paired box 3
Gene Synonym(s)	CDHS; HUP2; Pax-3; Pax-3; Sp; Splchl2; Splchl2; WS1; WS3; splotch; splotch-like 2
Strain of Origin	C57BL
Chromosome	1
Molecular Note	An A to T transversion at the invariant 3' AG splice acceptor of intron 3 was identified in this allele. This mutation abrogates the normal splicing of intron 3, resulting in the generation of four aberrantly spliced mRNA transcripts. Two of these Pax-3 transcripts make use of cryptic 3' splice sites within the downstream exon, generating small deletions which disrupt the reading frame of the transcripts. A third aberrant splicing event results in the deletion of exon 4, while a fourth retains intron 3. These aberrantly spliced mRNA transcripts are not expected to result in functional Pax3 proteins.

Disease/Phenotype

Disease Terms

Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested.

Research Areas By Genotype

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

Genotype: Pax3^Sp related

Dermatology Research
- Color and White Spotting Defects
Developmental Biology Research
- Neural Crest Defects
- Neural Tube Defects
Neurobiology Research
- Neural Tube Defects

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Pax3^Sp/Pax3⁺
C57BL-Pax3^Sp

pigmentation phenotype

belly spot

white spotting
- occasional spotting on the back and increased spotting on the tail compared to wild-type mice
- the feet are usually white

integument phenotype

belly spot

white spotting
- occasional spotting on the back and increased spotting on the tail compared to wild-type mice
- the feet are usually white

Genotype: Pax3^Sp/Pax3⁺
involves: C57BL * C57BL/6J * CBA

hearing/vestibular/ear phenotype

hearing/vestibular/ear phenotype
- auditory function and ear morphology are similar to wild type mice
- auditory function and ear morphology are similar to wild-type mice

Genotype: Pax3^Sp/Pax3⁺
involves: C3HeB * C57BL * C57BL/6J * SWV

nervous system phenotype

spina bifida
- increased incidence of spina bifida induced by in utero exposure to 50 mg/kg trans-retinoic acid compared to treated wild-type littermates

embryo phenotype

spina bifida
- increased incidence of spina bifida induced by in utero exposure to 50 mg/kg trans-retinoic acid compared to treated wild-type littermates

Genotype: Pax3^Sp/Pax3^Sp
involves: C57BL

mortality/aging

embryonic lethality during organogenesis, complete penetrance
- Background Sensitivity - mice die earlier compared to homozygotes on a congenic C57BR background
- die around E13-E14

muscle phenotype

abnormal dermomyotome development
- at E9.25, premature termination of the dermamyotome at the same level as the ventral lip of the axial myotome with absence of any epithelial structure in the ventral portion
- foreshortening of the epaxial domain and complete loss of the hypaxial domain of the dermomyotome at E10.5

abnormal muscle precursor cell migration
- DiI injections into the 3 somites immediately adjacent to the forelimb bud between E9.25 and E9.5 reveal impaired cell migration with no cell moving more than 30 - 40 um from the site of injection

abnormal myogenesis
- at E10.5 Pax3 expressing cells are absent from the forelimb and hindlimb buds
- at E12.5 expression of muscle specific markers myogenin and acetylcholinesterase are absent from the forelimb buds and expression of acetylcholinesterase is also absent from the hindlimb buds
- however, cells from somites grafted into chick limbs are able to undergo myogenic differentiation
- lack myogenic cells in the forming limb buds and hypoglossal cord at E11.5
- limb buds from E11 embryos cultured for 4 days fail to generate any cells expressing early myogenic markers (desmin and sarcomeric myosin)

nervous system phenotype

open neural tube
- 10 of 13 had open neural tube in sacro-caudal and cranial regions while in the other 3 the defect was confined to the sacro-caudal region

spina bifida
- treatment with folate solution of heterozygous females crossed to heterozygous males results in 40% decrease in spina bifida incidence in homozygous embryos examined at midgestation

hearing/vestibular/ear phenotype

abnormal bony labyrinth
- all labyrinth structures are abnormal in mice where the neural tube defect extend into the cranial region; however in mice with only sacro-caudal neural tube defects ear morphology is normal

abnormal endolymphatic duct morphology
- at E10, the origin of endolymphatic duct is shifted backwards and upwards and the duct is shorter and conical in shape
- at E11 the duct extends backwards and outwards rather than vertically upwards as in wild-type mice

abnormal otic vesicle development
- in mice where the neural tube defect extends to the cranial region

abnormal semicircular canal morphology
- present but abnormally located in terms of their planes, point of origin, and relationship to other structures in the labyrinth

abnormal utricle morphology
- difficult to distinguish and highly abnormal

abnormal vestibular saccule morphology
- difficult to distinguish and highly abnormal

decreased cochlear coiling
- at E12 cochlear coiling is poor

short endolymphatic duct
- at E10, the endolymphatic duct is shorter than normal

embryo phenotype

open neural tube
- 10 of 13 had open neural tube in sacro-caudal and cranial regions while in the other 3 the defect was confined to the sacro-caudal region

spina bifida
- treatment with folate solution of heterozygous females crossed to heterozygous males results in 40% decrease in spina bifida incidence in homozygous embryos examined at midgestation

cellular phenotype

abnormal muscle precursor cell migration
- DiI injections into the 3 somites immediately adjacent to the forelimb bud between E9.25 and E9.5 reveal impaired cell migration with no cell moving more than 30 - 40 um from the site of injection

Genotype: Pax3^Sp/Pax3^Sp
involves: 129S2/SvPas * C57BL * C57BL/6J * FVB

nervous system phenotype

increased embryonic neuroepithelium apoptosis
- many apoptotic neuroepithelial cells seen at the site of the neural tube defect

open neural tube
- seen in all mice
- treatment with pifithrin-alpha from E8.5 to E9.5 prevented neural tube defects in 55% of embryos

embryo phenotype

open neural tube
- seen in all mice
- treatment with pifithrin-alpha from E8.5 to E9.5 prevented neural tube defects in 55% of embryos

Genotype: Pax3^Sp/Pax3^Sp
C57BL-Pax3^Sp

mortality/aging

lethality throughout fetal growth and development, complete penetrance
- die around E14

nervous system phenotype

abnormal brain ventricle morphology
- at E10 or later, the lumen of the brain is highly distorted and partially collapsed or obliterated by the excessive overgrowth of neural tissue
- the lumen in the region of the myelencephalon and rhombencephalon are most sevely affected

abnormal dorsal root ganglion morphology
- in the region of the anterior limb buds spinal ganglia are absent or greatly reduced in size, disorganized, and abnormally located on the dorsal part of the neural tube
- the lumbo-sacral region spinal ganglia are usually absent

abnormal midbrain development
- at E10 and E11, mesencephalic ventricular cells display increased generation time, increased mitotic index, and prolonged mitosis, S phase, and G1
- the lumen in the mesencephalic region is greatly reduced and obscured by neural tissue

abnormal neural tube morphology
- neural overgrowth occurs laterad from the mid-dorsal line of the neural folds
- overgrowth of neural tissue in the region of the open neural tube is variable and becomes more pronounced with age
- ventricular cells in the upper lumbar neural tube and lower lumbar and sacral neural groove contain many gap junctional vesicles that are rarely seen in wild-type or heterozygous mice

open neural tube
- at E10 - E12.5, the extent to which the neural fold are open is highly variable ranging from just a small area in the lumbo-sacral region up to from the lumbo-sacral region to the tip of the tail
- at E9.5, neural folds are open in the hindlimb region with aggregation of neural tissue on both sides of the dorsal midline
- open neural folds generally limited to the hindbrain region are seen in about 56% of mice at E10, these are always associated with overgrowth of neural tissue
- open neural folds in the hindbrain region
- the extent of the area of open neural tube tends to increase in proportion to growth of the embryo

small embryonic telencephalon
- vesicles appear as a network of small channels

spina bifida

limbs/digits/tail phenotype

abnormal tail morphology
- distorted shape correlated to degree of rachischisis and neural overgrowth
- hematomas are frequently found in regions of tail curvature

kinked tail

pigmentation phenotype

absent coat pigmentation
- embryonic tissue explants allowed to develop until hair is formed display well developed hairs that are devoid of pigment

absent skin pigmentation
- embryonic tissue explants allowed to develop until the time when pigment would normally form are devoid of pigment

cellular phenotype

increased mitotic index
- at E10 and 11, mesencephalic ventricular cells have increased mitotic index compared to wild-type

embryo phenotype

abnormal neural tube morphology
- neural overgrowth occurs laterad from the mid-dorsal line of the neural folds
- overgrowth of neural tissue in the region of the open neural tube is variable and becomes more pronounced with age
- ventricular cells in the upper lumbar neural tube and lower lumbar and sacral neural groove contain many gap junctional vesicles that are rarely seen in wild-type or heterozygous mice

open neural tube
- at E10 - E12.5, the extent to which the neural fold are open is highly variable ranging from just a small area in the lumbo-sacral region up to from the lumbo-sacral region to the tip of the tail
- at E9.5, neural folds are open in the hindlimb region with aggregation of neural tissue on both sides of the dorsal midline
- open neural folds generally limited to the hindbrain region are seen in about 56% of mice at E10, these are always associated with overgrowth of neural tissue
- open neural folds in the hindbrain region
- the extent of the area of open neural tube tends to increase in proportion to growth of the embryo

spina bifida

integument phenotype

absent coat pigmentation
- embryonic tissue explants allowed to develop until hair is formed display well developed hairs that are devoid of pigment

absent skin pigmentation
- embryonic tissue explants allowed to develop until the time when pigment would normally form are devoid of pigment

Genotype: Pax3^Sp/Pax3^Sp
BR.B-Pax3^Sp

mortality/aging

perinatal lethality, complete penetrance
- Background Sensitivity - mice die later compared to mice on a mixed genetic background that includes C57BL
- die around E18-E19

nervous system phenotype

spina bifida cystica
- spina bifida aperta in the lumbosacral area

embryo phenotype

spina bifida cystica
- spina bifida aperta in the lumbosacral area

References

Additional References

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Epstein JA; Li J; Lang D; Chen F; Brown CB; Jin F; Lu MM; Thomas M; Liu E; Wessels A; Lo CW. 2000. Migration of cardiac neural crest cells in Splotch embryos. Development 127(9):1869-78. PubMed: 10751175 MGI: J:61431
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Goulding M; Sterrer S; Fleming J; Balling R; Nadeau J; Moore KJ; Brown SD; Steel KP; Gruss P. 1993. Analysis of the Pax-3 gene in the mouse mutant splotch. Genomics 17(2):355-63. PubMed: 8406486 MGI: J:13559
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Additional - Pax3^Sp related

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Brown CB; Feiner L; Lu MM; Li J; Ma X; Webber AL; Jia L; Raper JA; Epstein JA. 2001. PlexinA2 and semaphorin signaling during cardiac neural crest development. Development 128(16):3071-80. PubMed: 11688557 MGI: J:71241
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Daston G; Lamar E; Olivier M; Goulding M. 1996. Pax-3 is necessary for migration but not differentiation of limb muscle precursors in the mouse. Development 122(3):1017-27. PubMed: 8631247 MGI: J:32016
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Epstein JA; Li J; Lang D; Chen F; Brown CB; Jin F; Lu MM; Thomas M; Liu E; Wessels A; Lo CW. 2000. Migration of cardiac neural crest cells in Splotch embryos. Development 127(9):1869-78. PubMed: 10751175 MGI: J:61431
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Genetic overview

Research Applications

Detailed Description

Pax3Sp

Allele Symbol: Pax3Sp

Disease Terms

Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested.

Research Areas By Genotype

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

Genotype: Pax3Sp related

Mammalian Phenotype Terms by Genotype

Genotype: Pax3Sp/Pax3+C57BL-Pax3Sp

pigmentation phenotype

integument phenotype

Genotype: Pax3Sp/Pax3+involves: C57BL * C57BL/6J * CBA

hearing/vestibular/ear phenotype

Genotype: Pax3Sp/Pax3+involves: C3HeB * C57BL * C57BL/6J * SWV

nervous system phenotype

embryo phenotype

Genotype: Pax3Sp/Pax3Spinvolves: C57BL

mortality/aging

muscle phenotype

nervous system phenotype

hearing/vestibular/ear phenotype

embryo phenotype

cellular phenotype

Genotype: Pax3Sp/Pax3Spinvolves: 129S2/SvPas * C57BL * C57BL/6J * FVB

nervous system phenotype

embryo phenotype

Genotype: Pax3Sp/Pax3SpC57BL-Pax3Sp

mortality/aging

nervous system phenotype

limbs/digits/tail phenotype

pigmentation phenotype

cellular phenotype

embryo phenotype

integument phenotype

Genotype: Pax3Sp/Pax3SpBR.B-Pax3Sp

mortality/aging

nervous system phenotype

embryo phenotype

References

Additional References

Additional - Pax3Sp related

Genotyping Protocols

Appearance

Terms of Use

Licensing Information

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Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

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Pax3^Sp

Allele Symbol: Pax3^Sp

Genotype: Pax3^Sp related

Genotype: Pax3^Sp/Pax3⁺
C57BL-Pax3^Sp

Genotype: Pax3^Sp/Pax3⁺
involves: C57BL * C57BL/6J * CBA

Genotype: Pax3^Sp/Pax3⁺
involves: C3HeB * C57BL * C57BL/6J * SWV

Genotype: Pax3^Sp/Pax3^Sp
involves: C57BL

Genotype: Pax3^Sp/Pax3^Sp
involves: 129S2/SvPas * C57BL * C57BL/6J * FVB

Genotype: Pax3^Sp/Pax3^Sp
C57BL-Pax3^Sp

Genotype: Pax3^Sp/Pax3^Sp
BR.B-Pax3^Sp

Additional - Pax3^Sp related