TY - JOUR
T1 - Bmi-1 over-expression in neural stem/progenitor cells increases proliferation and neurogenesis in culture but has little effect on these functions in vivo
AU - He, Shenghui
AU - Iwashita, Toshihide
AU - Buchstaller, Johanna
AU - Molofsky, Anna V.
AU - Thomas, Dafydd
AU - Morrison, Sean J.
N1 - Funding Information:
This work was supported by the McDonnell Foundation and the Howard Hughes Medical Institute. Thanks to David Adams, Martin White, and Ann Marie Deslaurier of the University of Michigan (UM) Flow-Cytometry Core Facility. Flow-cytometry was supported in part by the UM Comprehensive Cancer Center NIH CA46592, and the UM Multipurpose Arthritis Center NIH AR20557. Thanks to Amanda Welton and the UM Center for Molecular Imaging for help with MRI analysis. Thanks to Galina Gavrilina and Thom Saunders of the UM Transgenic Animal Core Facility for generating Nestin-Bmi-1-HA-GFP transgenic mice with partial financial support from the UM Comprehensive Cancer Center NIH CA46592, the UM Center for Organogenesis, and the Michigan Economic Development Corporation (grant 085P1000815). Thanks to Daisuke Nakada for technical assistance with southern and western blotting.
PY - 2009/4/15
Y1 - 2009/4/15
N2 - The polycomb gene Bmi-1 is required for the self-renewal of stem cells from diverse tissues, including the central nervous system (CNS). Bmi-1 expression is elevated in most human gliomas, irrespective of grade, raising the question of whether Bmi-1 over-expression is sufficient to promote self-renewal or tumorigenesis by CNS stem/progenitor cells. To test this we generated Nestin-Bmi-1-GFP transgenic mice. Analysis of two independent lines with expression in the fetal and adult CNS demonstrated that transgenic neural stem cells formed larger colonies, more self-renewing divisions, and more neurons in culture. However, in vivo, Bmi-1 over-expression had little effect on CNS stem cell frequency, subventricular zone proliferation, olfactory bulb neurogenesis, or neurogenesis/gliogenesis during development. Bmi-1 transgenic mice were born with enlarged lateral ventricles and a minority developed idiopathic hydrocephalus as adults, but none of the transgenic mice formed detectable CNS tumors, even when aged. The more pronounced effects of Bmi-1 over-expression in culture were largely attributable to the attenuated induction of p16Ink4a and p19Arf in culture, proteins that are generally not expressed by neural stem/progenitor cells in young mice in vivo. Bmi-1 over-expression therefore has more pronounced effects in culture and does not appear to be sufficient to induce tumorigenesis in vivo.
AB - The polycomb gene Bmi-1 is required for the self-renewal of stem cells from diverse tissues, including the central nervous system (CNS). Bmi-1 expression is elevated in most human gliomas, irrespective of grade, raising the question of whether Bmi-1 over-expression is sufficient to promote self-renewal or tumorigenesis by CNS stem/progenitor cells. To test this we generated Nestin-Bmi-1-GFP transgenic mice. Analysis of two independent lines with expression in the fetal and adult CNS demonstrated that transgenic neural stem cells formed larger colonies, more self-renewing divisions, and more neurons in culture. However, in vivo, Bmi-1 over-expression had little effect on CNS stem cell frequency, subventricular zone proliferation, olfactory bulb neurogenesis, or neurogenesis/gliogenesis during development. Bmi-1 transgenic mice were born with enlarged lateral ventricles and a minority developed idiopathic hydrocephalus as adults, but none of the transgenic mice formed detectable CNS tumors, even when aged. The more pronounced effects of Bmi-1 over-expression in culture were largely attributable to the attenuated induction of p16Ink4a and p19Arf in culture, proteins that are generally not expressed by neural stem/progenitor cells in young mice in vivo. Bmi-1 over-expression therefore has more pronounced effects in culture and does not appear to be sufficient to induce tumorigenesis in vivo.
KW - Bmi-1
KW - Central nervous system (CNS)
KW - Glioblastoma
KW - Glioma
KW - Over-expression
KW - Stem cell
KW - Transgenic mouse
KW - Tumorigenesis
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U2 - 10.1016/j.ydbio.2009.01.020
DO - 10.1016/j.ydbio.2009.01.020
M3 - Article
C2 - 19389366
AN - SCOPUS:63549087793
SN - 0012-1606
VL - 328
SP - 257
EP - 272
JO - Developmental Biology
JF - Developmental Biology
IS - 2
ER -