All Phenotypes Cited2<tm1Jpmb> MGI Mouse

lethality throughout fetal growth and development, complete penetrance ( J:74736 )

• homozygotes first exhibit lethality at ~13.5 d.p.c

• by 18.5 d.p.c., most homozygotes are dead or moribund; 1 homozygote found dead on the day of birth

abnormal truncus arteriosus septation ( J:74736 )

• from 14.5 dpc onwards, homozygotes exhibit multiple severe defects in the outflow tract (full penetrance)

• 9 of 28 mutant embryos show RAI and RPI in combination with a common atrium and defects of the atrioventricular junction, ventricular septum, outflow tract and pharyngeal arch arteries

• 15 of 28 mutant embryos do not display isomerism

• 4 of these 15 display a foramen primum and defects of the atrioventricular junction, ventricular septum, outflow tract and pharyngeal arch arteries

• 8 of these 15 display outflow tract malformations, frequently in combination with muscular ventricular septal defects

• 3 of these 15, exhibit multiple ventricular septal defects only

• finally, 4 display a normal cardiac phenotype

abnormal atrioventricular cushion morphology ( J:97216 )

• at 14.5 dpc, mutant endocardial cushions of the atrioventricular canal appear defective

• at 10.5 dpc, the average cell density of endocardial cushions is significantly reduced

decreased atrioventricular cushion size ( J:97216 )

• at 10.5 dpc, the area of mutant endocardial cushions appears to be reduced

• however, the overall size of mutant hearts is relatively unaffected

abnormal direction of heart looping ( J:97216 )

• at 9.5-12.5 dpc, about 50% (52 of 115) of mutant embryos display abnormalities in cardiac looping

• 40 of 52 embryos have leftward (L) looped hearts; in most cases, ventricles are located on the left side of the midline of the embryo

• 12 of 52 embryos display abnormal D-looped hearts, with both ventricles on the right side of the midline

right atrial isomerism ( J:97216 )

• all mutant embryos with an abnormally looped heart display right atrial isomerism (RAI)

ventricular septal defect ( J:74736 )

• from 14.5 dpc onwards, homozygotes exhibit multiple severe abnormalities in the ventricular septum (full penetrance)

abnormal basicranium morphology ( J:97216 )

• at 15.5 dpc, the base of the mutant skull is present but malformed

abnormal neurocranium morphology ( J:74736 )

• at 15.5 dpc, the developing bones of the mutant skull vault are absent

decreased fetal size ( J:74736 )

• from 14.5 dpc onwards, homozygous mutant embryos are frequently smaller than wild-type

right-sided isomerism ( J:97216 )

• 9 of 28 mutant embryos show RAI and RPI in combination with a common atrium and defects of the atrioventricular junction, ventricular septum, outflow tract and pharyngeal arch arteries

right atrial isomerism ( J:97216 )

• all mutant embryos with an abnormally looped heart display right atrial isomerism (RAI)

right pulmonary isomerism ( J:97216 )

• all mutant embryos with RAI display right pulmonary isomerism (RPI), i.e. 4 lung lobes on both sides

homeostasis/metabolism phenotype ( J:74736 )

N	• homozygotes display normal folate metabolism relative to wild-type

edema ( J:74736 )

• from 14.5 dpc onwards, homozygotes display edema in the cervical region

abnormal basicranium morphology ( J:97216 )

• at 15.5 dpc, the base of the mutant skull is present but malformed

abnormal neurocranium morphology ( J:74736 )

• at 15.5 dpc, the developing bones of the mutant skull vault are absent

increased embryonic neuroepithelium apoptosis ( J:74736 )

• homozygotes with NTD defects show increased apoptosis within the neuroectoderm at the FB-MB boundary and hindbrain level

• notably, folic acid administration does not reduce cell death in these regions

open neural tube ( J:74736 )

• starting at 8.5 dpc, homozygotes exhibit abnormal separation of neural folds at the forebrain (FB)-midbrain (MB) boundary

• at 9.5 dpc, homozygotes show variable degrees of neural tube defects (NTD) ranging from none to severe NTDs affecting the FB, MB and hindbrain; overall, ~50% of homozygotes show some degree of NTD

• at 10.5 dpc, ~80% of homozygotes show the outward expansion of cranial neuroectoderm and are exencephalic; the remaining 20% exhibit a closed neural tube

exencephaly ( J:74736 )

• at 14.5-16.5 dpc, ~80% of homozygotes display exencephaly of the entire brain

• at 14.5-16.5 dpc, exencephalic mutants display undeveloped telencephalic vesicles and diencephalon are surrounded by the everted neuroectoderm of the midbrain and hindbrain; other regions of the neural tube remain unaffected

• folic acid treatment significantly reduces the exencephalic phenotype both in vivo and in vitro

abnormal cranial ganglia morphology ( J:74736 )

• at 14.5 dpc, the mutant trigeminal (V), facioacoustic (VII and VIII), glossopharyngeal (IX) and vagus (X) ganglia are smaller in size relative to wild-type

fused dorsal root ganglion ( J:74736 )

• at 14.5 dpc, the mutant dorsal root ganglion appears to be fused in the cervical region

abnormal left-right axis patterning ( J:97216 )

• mutant embryos exhibit left-right-patterning defects, as shown by abnormal expression of left sided determinants

• one-third of mutant embryos show loss of Nodal, Lefty2 and Pitx2 expression in the left lateral plate mesoderm, and loss of Lefty1 expression in the anterior prospective floor plate

abnormal neural fold formation ( J:74736 )

• at 9.5 dpc, the neural folds display a concave morphology and converge towards the midline

• in severely affected homozygotes, the neural folds of the MB and rostral hindbrain are horizontal and wide-open