Bcl-XL/Bax proteins direct the fate of embryonic cortical precursor cells.
In the developing mouse brain, the highest Bcl-X(L) expression is seen at the peak of neurogenesis, whereas the peak of Bax expression coincides with the astrogenic period. While such observations suggest an active role of the Bcl-2 family proteins in the generation of neurons and astrocytes, no definitive demonstration has been provided to date. Using combinations of gain- and loss-of-function assays in vivo and in vitro, we provide evidence for instructive roles of these proteins in neuronal and astrocytic fate specification. Specifically, in Bax knockout mice, astrocyte formation was decreased in the developing cortices. Overexpression of Bcl-X(L) and Bax in embryonic cortical precursors induced neural and astrocytic differentiation, respectively, while inhibitory RNAs led to the opposite results. Importantly, inhibition of caspase activity, dimerization, or mitochondrial localization of Bcl-X(L)/Bax proteins indicated that the differentiation effects of Bcl-X(L)/Bax are separable from their roles in cell survival and apoptosis. Lastly, we describe activation of intracellular signaling pathways and expression of basic helix-loop-helix transcriptional factors specific for the Bcl-2 protein-mediated differentiation.
Chang
Mi-Yoon
MY
Department of Biochemistry & Molecular Biology, College of Medicine, Hanyang University, 17 Haengdang-Dong, Sungdong-Gu, Seoul, South Korea.
Sun
Woong
W
Ochiai
Wataru
W
Nakashima
Kinichi
K
Kim
Soo-Young
SY
Park
Chang-Hwan
CH
Kang
Jin Sun
JS
Shim
Jae-Won
JW
Jo
A-Young
AY
Kang
Chun-Sik
CS
Lee
Yong-Sung
YS
Kim
Jae-Sang
JS
Lee
Sang-Hun
SH
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D061945:Caspase Inhibitors; D002454:Cell Differentiation; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000196:embryology*; D020099:Coated Materials, Biocompatible / Q000378:metabolism; D003433:Crosses, Genetic; D019281:Dimerization; D004789:Enzyme Activation; D005353:Fibronectins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006720:Homozygote; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009474:Neurons / Q000166:cytology / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D014161:Transduction, Genetic; D051028:bcl-2-Associated X Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D061945:Caspase Inhibitors; D020099:Coated Materials, Biocompatible; D005353:Fibronectins; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein