| Autor: |
Veleta KA; UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC, 27599, USA., Cleveland AH; UNC Cancer Cell Biology Training Program, University of North Carolina, Chapel Hill, NC, 27599, USA., Babcock BR; Department of Neurology, UNC School of Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA., He YW; Department of Immunology, Duke University, Durham, NC, 27708, USA., Hwang D; Center for Nanotechnology in Drug Delivery and Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA., Sokolsky-Papkov M; Center for Nanotechnology in Drug Delivery and Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA., Gershon TR; UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC, 27599, USA. gershont@neurology.med.unc.edu.; Department of Neurology, UNC School of Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA. gershont@neurology.med.unc.edu.; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA. gershont@neurology.med.unc.edu. |
| Abstrakt: |
The tendency of brain cells to undergo apoptosis in response to exogenous events varies across neural development, with apoptotic threshold dependent on proliferation state. Proliferative neural progenitors show a low threshold for apoptosis, while terminally differentiated neurons are relatively refractory. To define the mechanisms linking proliferation and apoptotic threshold, we examined the effect of conditionally deleting Bcl2l1, the gene that codes the antiapoptotic protein BCL-xL, in cerebellar granule neuron progenitors (CGNPs), and of co-deleting Bcl2l1 homologs, antiapoptotic Mcl-1, or pro-apoptotic Bax. We found that cerebella in conditional Bcl2l1-deleted (Bcl-xL cKO ) mice were severely hypoplastic due to the increased apoptosis of CGNPs and their differentiated progeny, the cerebellar granule neurons (CGNs). Apoptosis was highest as Bcl-xL cKO CGNPs exited the cell cycle to initiate differentiation, with proliferating Bcl-xL cKO CGNPs relatively less affected. Despite the overall reduction in cerebellar growth, SHH-dependent proliferation was prolonged in Bcl-xL cKO mice, as more CGNPs remained proliferative in the second postnatal week. Co-deletion of Bax rescued the Bcl-xL cKO phenotype, while co-deletion of Mcl-1 enhanced the phenotype. These findings show that CGNPs require BCL-xL to regulate BAX-dependent apoptosis, and that this role can be partially compensated by MCL-1. Our data further show that BCL-xL expression regulates MCL-1 abundance in CGNPs, and suggest that excessive MCL-1 in Bcl-xL cKO mice prolongs CGNP proliferation by binding SUFU, resulting in increased SHH pathway activation. Accordingly, we propose that BCL-xL and MCL-1 interact with each other and with developmental mechanisms that regulate proliferation, to adjust the apoptotic threshold as CGNPs progress through postnatal neurogenesis to CGNs. |
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