Mcl-1 is a key regulator of apoptosis during CNS development and after DNA damage.
Despite the importance of Mcl-1, an anti-apoptotic Bcl-2 family member, in the regulation of apoptosis, little is known regarding its role in nervous system development and injury-induced neuronal cell death. Because germline deletion of Mcl-1 results in peri-implantation lethality, we address the function of Mcl-1 in the nervous system using two different conditional Mcl-1 mouse mutants in the developing nervous system. Here, we show for the first time that Mcl-1 is required for neuronal development. Neural precursors within the ventricular zone and newly committed neurons in the cortical plate express high levels of Mcl-1 throughout cortical neurogenesis. Loss of Mcl-1 in neuronal progenitors results in widespread apoptosis. Double labeling with active caspase 3 and Tuj1 reveals that newly committed Mcl1 deficient neurons undergo apoptosis as they commence migration away from the ventricular zone. Examination of neural progenitor differentiation in vitro demonstrated that cell death in the absence of Mcl1 is cell autonomous. Although conditional deletion of Mcl-1 in cultured neurons does not trigger apoptosis, loss of Mcl-1 sensitizes neurons to an acute DNA damaging insult. Indeed, the rapid reduction of Mcl-1 mRNA and protein levels are early events after DNA damage in neurons, and maintaining high Mcl-1 levels can protect neurons against death. Together, our results are the first to demonstrate the requirement of Mcl-1, an anti-apoptotic Bcl-2 family protein, for cortical neurogenesis and the survival of neurons after DNA damage.
Department of Biochemistry, Microbiology, and Immunology, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
Nicole
N
Arbour
Jacqueline L
JL
Vanderluit
J Nicole
JN
Le Grand
Arezu
A
Jahani-Asl
Vladimir A
VA
Ruzhynsky
Eric C C
EC
Cheung
Melissa A
MA
Kelly
Alexander E
AE
MacKenzie
David S
DS
Park
Joseph T
JT
Opferman
Ruth S
RS
Slack
D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology / Q000196:embryology*; D004249:DNA Damage / Q000235:genetics / Q000502:physiology*; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology; D014162:Transfection / Q000379:methods; D014404:Tubulin / Q000378:metabolism
C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009419:Nerve Tissue Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014404:Tubulin; C462941:beta3 tubulin, mouse; D049452:Green Fluorescent Proteins; D053148:Caspase 3