Phenotypes associated with this allele

• Allele Symbol: Tfap2a^tm1Will
• Allele Name: targeted mutation 1, Trevor Williams
• Allele ID: MGI:2176682
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Tfap2a^tm1Will/Tfap2a^tm1Will	involves: Black Swiss	MGI:2176691
ht2	Tfap2a^tm1Will/Tfap2a^+	involves: Black Swiss	MGI:2176693
ht3	Tfap2a^tm1Will/Tfap2a^tm2.1Will	involves: 129S1/Sv * Black Swiss	MGI:5647995
cx4	Fgf8^tm1.4Mrt/Fgf8^+ Tfap2a^tm1Will/Tfap2a^tm2.1Will	involves: 129P2/OlaHsd * 129S1/Sv * Black Swiss	MGI:5648001

Genotype
MGI:2176691

hm1

• Allelic Composition: Tfap2a^tm1Will/Tfap2a^tm1Will
• Genetic Background: involves: Black Swiss

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

mortality/aging

perinatal lethality, complete penetrance ( J:33031 )

• homozygous null mice die at or before birth as a result of severe congenital defects

pigmentation

abnormal retina pigment epithelium morphology ( J:52402 )

• although a bilayered optic cup is formed, a retinal pigmented epithelium fails to develop on the dorsal side

• a pseudostratified neuroepithelial layer resembling neural retina is formed instead of RPE

cardiovascular system

abnormal aortic arch morphology ( J:73813 )

• three of five embryos showed abnormal aortic arch arteries

retroesophageal right subclavian artery ( J:73813 )

• three of five embryos showed abnormal aortic arch arteries: two had retroesophageal right subclavian artery

interrupted aortic arch ( J:73813 )

• three of five embryos showed abnormal aortic arch arteries

interrupted aortic arch, type b ( J:73813 )

• one embryo had type B interrupted aortic arch

abnormal truncus arteriosus septation ( J:73813 )

• all five mutant embryos studied (two at E14.5, two at E15.5, and one at full term) showed severe cardiac outflow tract malformations

persistent truncus arteriosus ( J:73813 )

• one mutant embryo exhibited persistent truncus arteriosus (PTA) subtype A2: complete failure to septate the outflow tract, with the persisting single vessel originating from the right ventricle through a single valvular apparatus

• the remaining embryo had PTA subtype A1: a fused valvular apparatus was present, but the septated aortic and pulmonary vessels were located distally

double outlet right ventricle ( J:73813 )

• in three out of five mutant embryos, the aortic and pulmonary outflow structures were normally formed (normal outflow tract septation), but both originated abnormally from the right ventricle

absent pericardium ( J:73813 )

• most mutant hearts are located within a normal pericardial cavity; in some embryos, no pericardial cavity is detected, although the surface of the heart is lined by epicardium

cellular

abnormal cell death ( J:33031 )

• failure of craniofacial development is accompanied by cell death associated with the trigeminal ganglia at E9.5, and with the face region at E12.5

craniofacial

abnormal cranium morphology ( J:33031 )

• homozygotes lack recognizable ventral craniofacial structures

abnormal neurocranium morphology ( J:33031 )

• the cranial vault is not distinguishable

abnormal mandible morphology ( J:33031 )

• the mutant mandibles remain unfused

absent maxilla ( J:33031 )

• the maxilla is not distinguishable

absent middle ear ossicles ( J:33031 )

• although the cochlea is present, middle-ear bones are not observed

absent mouth ( J:33031 )

absent snout ( J:33031 )

absent outer ear ( J:33031 )

embryo

embryo phenotype ( J:33031 )

N • at E8.5, mutant embryos display no gross anatomical abnormalities

abnormal dorsal-ventral axis patterning ( J:33031 )

• homozygotes show disrupted development and migration of the dorsolateral body wall that normally generates ventral surface

• mutants do not display a general failure of body wall formation, as the dorsal surface of the torso is covered by mature keratinized skin, containing hair follicles

endocrine/exocrine glands

endocrine/exocrine gland phenotype ( J:81338 )

N • mutant fetuses show normal norepinephrine and dopamine levels as well as normal dopa decarboxylase actvity in the adrenal and kidney

abnormal adrenal gland secretion ( J:81338 )

• relative to wild-type fetuses, mutant fetuses display a 66% reduction of adrenal phenylethanolamine N-methyltransferase (PNMT) activity, and a >50% decrease in adrenal epinephrine

• in the kidney, PNMT activity is reduced by 36% and kidney epinephrine is decreased by >70%

growth/size/body

thoracoabdominoschisis ( J:33031 )

• mutants exhibit thoracoabdominoschisis: the ventral body wall is absent, and abdominal and thoracic contents are exposed

abnormal head morphology ( J:33031 )

• by E12.5, the mutant mouse head is largely neurepithelium

absent mouth ( J:33031 )

absent snout ( J:33031 )

absent outer ear ( J:33031 )

decreased body size ( J:33031 )

• all homozygotes are runted, consistent with hypoplastic and retarded development of several tissues and organs, including the heart and kidney

hearing/vestibular/ear

absent middle ear ossicles ( J:33031 )

• although the cochlea is present, middle-ear bones are not observed

absent outer ear ( J:33031 )

absent tympanic ring ( J:33031 )

• the tympanic ring is absent

limbs/digits/tail

absent radius ( J:33031 )

• several mutants display forelimb defects: 18 of 28 mutant embryo forelimbs lacked a radius

skeleton

skeleton phenotype ( J:33031 )

N • the axis and atlas appear normal

N • the exoccipital, basioccipital and basisphenoid bones of the chordal skeleton are identifiable

abnormal cranium morphology ( J:33031 )

• homozygotes lack recognizable ventral craniofacial structures

abnormal neurocranium morphology ( J:33031 )

• the cranial vault is not distinguishable

abnormal mandible morphology ( J:33031 )

• the mutant mandibles remain unfused

absent maxilla ( J:33031 )

• the maxilla is not distinguishable

absent middle ear ossicles ( J:33031 )

• although the cochlea is present, middle-ear bones are not observed

absent radius ( J:33031 )

• several mutants display forelimb defects: 18 of 28 mutant embryo forelimbs lacked a radius

absent clavicle ( J:33031 )

• mutant skeletons lack clavicles

absent sternum ( J:33031 )

• the mutant rib cage fails to fuse to a central sternum

scoliosis ( J:33031 )

vision/eye

abnormal retina pigment epithelium morphology ( J:52402 )

• although a bilayered optic cup is formed, a retinal pigmented epithelium fails to develop on the dorsal side

• a pseudostratified neuroepithelial layer resembling neural retina is formed instead of RPE

aniridia ( J:52402 )

• anterior margins of the developing optic cup fail to form an iris and ciliary body

abnormal cornea morphology ( J:52402 )

• mutant embryos display absence of a developing cornea

abnormal lens morphology ( J:52402 )

• mutant lenses are malformed and remain connected to the overlying ectoderm via a lens stalk

• an anterior lens epithelium fails to develop

abnormal lens induction ( J:52402 )

• all mutant embryos which have eyes show abnormal lens induction

• lens induction fails completely in some mutants (33% of E11.5 and 14% of E12.5)

abnormal lens vesicle development ( J:52402 )

• the surface ectoderm which normally invaginates to form the lens vesicle is replaced by mesenchymal cells that occupy the inner aspect of the optic cup

• in most mutants (67% of E11.5; 43% of E12.5) the surface ectoderm has been induced to invaginate into the optic cup but lenses appear abnormal

small lens ( J:52402 )

abnormal optic fissure closure ( J:52402 )

• the optic stalk is often mislocated, with the choroidal fissure either delayed or failing to close

abnormal optic stalk morphology ( J:52402 )

• the optic stalk is often mislocated

absent eyelids ( J:52402 )

absent retina ganglion layer ( J:52402 )

• almost all mutant retinas show absence of a defined ganglion cell layer

anophthalmia ( J:52402 )

• at E9.5-E10.5, homozygotes have eyes on the surface of their head; however, all mutants examined at E12.5 and later fail to exhibit eyes

• 38% of mutant embryos completely lack either one or both eyes

• 62% of mutants have eyes or eye rudiments that are embedded inside the head and appear to be surrounded by an outgrowth of mesenchymal and neural tissue

nervous system

anencephaly ( J:33031 )

exencephaly ( J:33031 )

• at E9.5, the cranial neural folds remain widely separated, resulting in exencephaly

• closure of the spinal neural tube is normal

abnormal cochlear ganglion morphology ( J:33031 )

abnormal glossopharyngeal ganglion morphology ( J:33031 )

small trigeminal ganglion ( J:33031 )

• at E10.5, the trigeminal ganglion (V) is greatly reduced relative to wild-type; in contrast, the dorsal root ganglia appear normal

abnormal vagus ganglion morphology ( J:33031 )

abnormal vestibular ganglion morphology ( J:33031 )

abnormal cranial nerve morphology ( J:33031 )

• the morphologies of the VII/VIII ganglion complex, and IX and X ganglia and nerves, are disrupted with variable penetrance

abnormal facial nerve morphology ( J:33031 )

absent oculomotor nerve ( J:33031 )

• at E10.5, the oculomotor nerve is not observed

Genotype
MGI:2176693

ht2

• Allelic Composition: Tfap2a^tm1Will/Tfap2a⁺
• Genetic Background: involves: Black Swiss

hearing/vestibular/ear

hearing/vestibular/ear phenotype ( J:90701 )

N • heterozygotes display normal response to sudden sounds (Preyer reflex) and normal middle ear bone morphology

Genotype
MGI:5647995

ht3

• Allelic Composition: Tfap2a^tm1Will/Tfap2a^tm2.1Will
• Genetic Background: involves: 129S1/Sv * Black Swiss

mortality/aging

perinatal lethality ( J:217408 )

craniofacial

abnormal maxilla morphology ( J:217408 )

• changes in both the relative size and shape of the maxilla

• maxilla seems to grow away from the midface; at E11.5, the maxilla is located in a more rostrolateral position

• decrease in proliferation in the mesenchyme of the maxilla

abnormal premaxilla morphology ( J:217408 )

• the premaxilla is discontinuous in embryos, resulting in the premaxilla to protrude from the anterior of the face as a bulbous structure

abnormal craniofacial development ( J:217408 )

• changes in shape of both the nasal and maxillary prominences that places them in more lateral positions

abnormal lateral nasal prominence morphology ( J:217408 )

• decrease in proliferation in the mesenchyme of the medial and lateral nasal prominences

abnormal maxillary prominence morphology ( J:217408 )

• low penetrance (2 of 10) of defects in the maxillary palatal processes

• the maxillary prominence is projected laterally

• reduced rate of proliferation in the mesenchyme of the maxillary prominences

abnormal medial nasal prominence morphology ( J:217408 )

• decrease in proliferation in the mesenchyme of the medial and lateral nasal prominences

abnormal nasal pit morphology ( J:217408 )

• changes in both the relative size and shape of the nasal pit, with the lateral edge of the nasal pit flaring outward instead of growing in toward the center

• apoptotic cells are not seen where the medial and lateral edges of nasal pit ectoderm are beginning to fuse as in controls

abnormal facial morphology ( J:217408 )

• facial shape differences are apparent from E10.25 and morphologies become highly divergent by E11.5

• mice with exencephaly have a distinct facial morphology from mice with facial clefting but no exencephaly

abnormal secondary palate morphology ( J:217408 )

• the secondary-palate defects are mainly associated with defects in the premaxilla and the premaxillary palatal processes

cleft palate ( J:217408 )

• fully penetrant at E18.5

• both primary and secondary palates are affected, although defects in the more posterior regions of the secondary palate are not generally not seen

facial cleft ( J:217408 )

• E18.5 mice exhibit fully penetrant bilateral facial clefting (cleft lip/palate)

• failure of facial fusion is due to changes in the growth and morphogenesis of the facial prominences

• the lateral edge of the nasal pit flares outward instead of growing in toward the center and the maxillary prominence is projected laterally, preventing apposition and fusion of the facial prominences

embryo

abnormal neural tube closure ( J:217408 )

• about 45% of mice exhibit abnormal neural tube closure at E9.5

growth/size/body

abnormal facial morphology ( J:217408 )

• facial shape differences are apparent from E10.25 and morphologies become highly divergent by E11.5

• mice with exencephaly have a distinct facial morphology from mice with facial clefting but no exencephaly

abnormal secondary palate morphology ( J:217408 )

• the secondary-palate defects are mainly associated with defects in the premaxilla and the premaxillary palatal processes

cleft palate ( J:217408 )

• fully penetrant at E18.5

• both primary and secondary palates are affected, although defects in the more posterior regions of the secondary palate are not generally not seen

facial cleft ( J:217408 )

• E18.5 mice exhibit fully penetrant bilateral facial clefting (cleft lip/palate)

• failure of facial fusion is due to changes in the growth and morphogenesis of the facial prominences

• the lateral edge of the nasal pit flares outward instead of growing in toward the center and the maxillary prominence is projected laterally, preventing apposition and fusion of the facial prominences

limbs/digits/tail

polydactyly ( J:217408 )

digestive/alimentary system

abnormal secondary palate morphology ( J:217408 )

• the secondary-palate defects are mainly associated with defects in the premaxilla and the premaxillary palatal processes

cleft palate ( J:217408 )

• fully penetrant at E18.5

• both primary and secondary palates are affected, although defects in the more posterior regions of the secondary palate are not generally not seen

nervous system

abnormal neural tube closure ( J:217408 )

• about 45% of mice exhibit abnormal neural tube closure at E9.5

exencephaly ( J:217408 )

• about 30% of E18.5 mice exhibit mid/hindbrain exencephaly

respiratory system

abnormal nasal pit morphology ( J:217408 )

• changes in both the relative size and shape of the nasal pit, with the lateral edge of the nasal pit flaring outward instead of growing in toward the center

• apoptotic cells are not seen where the medial and lateral edges of nasal pit ectoderm are beginning to fuse as in controls

skeleton

abnormal maxilla morphology ( J:217408 )

• changes in both the relative size and shape of the maxilla

• maxilla seems to grow away from the midface; at E11.5, the maxilla is located in a more rostrolateral position

• decrease in proliferation in the mesenchyme of the maxilla

abnormal premaxilla morphology ( J:217408 )

• the premaxilla is discontinuous in embryos, resulting in the premaxilla to protrude from the anterior of the face as a bulbous structure

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
orofacial cleft		DOID:0050567	OMIM:PS119530	J:217408

Genotype
MGI:5648001

cx4

• Allelic Composition: Fgf8^tm1.4Mrt/Fgf8⁺; Tfap2a^tm1Will/Tfap2a^tm2.1Will
• Genetic Background: involves: 129P2/OlaHsd * 129S1/Sv * Black Swiss

craniofacial

abnormal nasal pit morphology ( J:217408 )

• the nasal pits are somewhat larger and are angled slightly downwards toward the maxilla

abnormal midface morphology ( J:217408 )

• slight widening of the midface

cleft primary palate ( J:217408 )

• 8 of 18 mice exhibit a unilateral premaxillary fusion defect resulting in a unilateral cleft primary palate

unilateral cleft palate ( J:217408 )

digestive/alimentary system

cleft primary palate ( J:217408 )

• 8 of 18 mice exhibit a unilateral premaxillary fusion defect resulting in a unilateral cleft primary palate

unilateral cleft palate ( J:217408 )

growth/size/body

abnormal midface morphology ( J:217408 )

• slight widening of the midface

cleft primary palate ( J:217408 )

• 8 of 18 mice exhibit a unilateral premaxillary fusion defect resulting in a unilateral cleft primary palate

unilateral cleft palate ( J:217408 )

respiratory system

abnormal nasal pit morphology ( J:217408 )

• the nasal pits are somewhat larger and are angled slightly downwards toward the maxilla