Analysis Tools
mortality/aging
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• 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
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cardiovascular system
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• from 14.5 dpc onwards, homozygotes exhibit multiple severe defects in the outflow tract (full penetrance)
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• 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
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• 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
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• at 10.5 dpc, the area of mutant endocardial cushions appears to be reduced
• however, the overall size of mutant hearts is relatively unaffected
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• 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
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• all mutant embryos with an abnormally looped heart display right atrial isomerism (RAI)
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• from 14.5 dpc onwards, homozygotes exhibit multiple severe abnormalities in the ventricular septum (full penetrance)
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craniofacial
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• at 15.5 dpc, the base of the mutant skull is present but malformed
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• at 15.5 dpc, the developing bones of the mutant skull vault are absent
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growth/size/body
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• from 14.5 dpc onwards, homozygous mutant embryos are frequently smaller than wild-type
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• 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
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• all mutant embryos with an abnormally looped heart display right atrial isomerism (RAI)
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• all mutant embryos with RAI display right pulmonary isomerism (RPI), i.e. 4 lung lobes on both sides
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homeostasis/metabolism
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• homozygotes display normal folate metabolism relative to wild-type
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skeleton
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• at 15.5 dpc, the base of the mutant skull is present but malformed
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• at 15.5 dpc, the developing bones of the mutant skull vault are absent
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nervous system
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• 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
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• 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
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exencephaly
(
J:74736
)
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• 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
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• 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
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• at 14.5 dpc, the mutant dorsal root ganglion appears to be fused in the cervical region
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embryo
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• 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
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• 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
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• 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
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digestive/alimentary system
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• in 8 of 14 mutant embryos, the stomach is abnormally located in the midline or on the right hand side
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respiratory system
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• all mutant embryos with RAI display right pulmonary isomerism (RPI), i.e. 4 lung lobes on both sides
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cellular
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• 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
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