Mouse Genome Informatics
cx
    Tg(Tek-tTA)1Rwng/0
Tg(tetO-Notch4*)1Rwng/0

involves: FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       
mortality/aging
• die between 2 and 5 weeks of age

behavior/neurological
• ataxia ranging in severity from mice being unable to right themselves to those with splayed rear legs
• mice occasionally exhibit seizure episodes in which they run wildly before collapsing

cardiovascular system
• arteries, veins, and intervening vessels of the middle-cerebral vessels are enlarged
• vessel enlargement occurs before hemorrhage, neuronal cell death, or signs of neurological dysfunction
• vessel enlargement correlates with hemorrhage, with them most large vessels in the cerebellum, followed by neocortex
• vessel density is decreased significantly in the cerebellum, and progressively less so in the neocortex and brainstem
• enlarged and tangled vessels resembling brain arteriovenous malformations
• arteriovenous shunts in the brain
• hemorrhage in the brain of all mutants, most often in the cerebellum, followed by the neocortex, but never in the brainstem
• hemorrhage is more widespread than neurological dysfunction, seen in all ill mutants without ataxia and is most severe in mice ill before P22
• blood is seen in the ventricle of 4 of 11 ill mice before P21
• increase in carotid blood velocity in all mutants by 3 weeks of age
• carotid blood velocity increases between P17 and P21 and at P21, velocity in mutants with neurological dysfunction is higher than mutants without the dysfunction

homeostasis/metabolism
• thrombosis is seen in hemorrhagic areas

nervous system
• signs of calcification in the brain
• arteries, veins, and intervening vessels of the middle-cerebral vessels are enlarged
• vessel enlargement occurs before hemorrhage, neuronal cell death, or signs of neurological dysfunction
• vessel enlargement correlates with hemorrhage, with them most large vessels in the cerebellum, followed by neocortex
• vessel density is decreased significantly in the cerebellum, and progressively less so in the neocortex and brainstem
• foci of pyknotic and karyorectic nuclei in the midbrain
• macrophage infiltrations in the midbrain
• foci of pyknotic and karyorectic nuclei in the neocortex
• macrophage infiltrations in the neocortex
• foci of pyknotic and karyorectic nuclei in the Purkinje and granular layers of the cerebellum
• macrophage infiltrations in the Purkinje and granular layers of the cerebellum
• neurological dysfunction is seen in 27 of 107 mutants, including ataxia and seizures
• all but one of the cases of ataxia and seizure occur before P22
• sick mutants at P20-21 treated with doxycycline to repress Notch4 expression appear healthy and active at P35 and P64
• mice occasionally exhibit seizure episodes in which they run wildly before collapsing
• blood is seen in the ventricle of 4 of 11 ill mice before P21
• neuronal cell death adjacent to hemorrhage

cellular
• neuronal cell death adjacent to hemorrhage

Mouse Models of Human Disease
OMIM IDRef(s)
Arteriovenous Malformations of the Brain 108010 J:139943