In vivo inactivation of pRb, p107 and p130 in murine neuroprogenitor cells leads to major CNS developmental defects and high seizure rates.
Nestin-positive cells were targeted for pRb, p107 and p130 (pRb(f)) inactivation by expression of T(121), a truncated SV40 large T antigen that selectively binds to and inactivates pRb(f). Cre expression was initiated under GFAP control, resulting in T(121) expression restricted to neuroprogenitor cells beginning at embryonic day 11.5 (E11.5). Bi-transgenic embryos showed aberrant central nervous system (CNS) cell proliferation and apoptosis by E13.5. Defects in cortical development were evident with primary effects resulting in depletion of neural progenitors and aberrant cellular migration. Consequently, juvenile and adult brain morphology was reproducibly abnormal, including disorganization of neocortical, hippocampal and cerebellar regions. These aberrations resulted in behavioral phenotypes, including ataxia and seizures. The data indicate that inactivation of pRb(f) in radial glial cells, a population of neuroprogenitor cells, leads to specific disruptions in CNS patterning. The neuroprogenitor-restricted transgene expression provides a model in which to explore both developmental mechanisms and functional neurological outcomes.
McLear
Julie A
JA
Curriculum in Neurobiology, UNC Neuroscience Center and Neurodevelopmental Disorders Research Center, Chapel Hill, NC 27599-7295, USA.
Garcia-Fresco
German
G
Bhat
Manzoor A
MA
Van Dyke
Terry A
TA
D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000502:physiology; D002490:Central Nervous System / Q000002:abnormalities / Q000196:embryology / Q000254:growth & development; D004622:Embryo, Mammalian; D005455:Fluorescent Antibody Technique / Q000379:methods; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics; D064231:Nestin; D009474:Neurons / Q000378:metabolism*; D050720:Retinoblastoma-Like Protein p107 / Q000235:genetics / Q000378:metabolism*; D050717:Retinoblastoma-Like Protein p130 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012640:Seizures / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism*
D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; C493837:RBL2 protein, human; C493838:Rbl2 protein, mouse; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D049452:Green Fluorescent Proteins