| Abstract No.: | C-A3008 |
| Country: | Canada |
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| Title: | MCL-1 IS A KEY REGULATOR OF APOPTOSIS IN NEURAL PRECURSOR CELLS. |
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| Authors/Affiliations: | 1 Jacqueline Vanderluit*; 3 Nicole Arbour; 3 Nicole Legrand; 3 Arezu Jahani-Asl; 3 Vladimir Ruzhynsky; 3 Eric Cheung; 3 Melissa Kelly; 2 Joseph Opferman; 3 Ruth Slack;
1 Memorial University, St. John's, NL, Canada; 2 St. Jude Research Hospital, Memphis, TN, USA; 3 University of Ottawa, ON, Canada
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| Content: | Neural precursor cell numbers are regulated by a balance between proliferation and apoptosis. The Bcl-2 family of apoptotic and anti-apoptotic proteins has been shown to play an integral role in the regulation of apoptotic cell death. Mcl-1, an anti-apoptotic member of the Bcl-2 family, is a known survival factor for hematopoietic stem cells, however little is known regarding its function in the nervous system.
Objective: The objective of this study is to identify the role of Mcl-1 in nervous system development and specifically determine whether it functions as a survival factor in neural precursor cells.
Materials & Methods: Due to the embryonic lethality of germline Mcl-1 knockout mice at E3.5, we used mice with conditional mutations in Mcl-1 in neural precursor cells to address the role of Mcl-1 in nervous system development.
Results: Here we show for the first time that Mcl-1 is required for neural development. Loss of Mcl-1 in neuronal progenitors results in a dramatic loss of neural precursors and embryonic lethality at E15-16. To determine at what stage in progenitor cell development (progenitor cell → migratory neuroblast → committed neuron) cells require Mcl-1 for survival, we performed double immunohistochemistry with active caspase 3 (AC3) and stage specific markers. One third of the AC3+ cells were Nestin+ neural progenitor cells, the majority of cells (>60%) were Doublecortin+ migratory neuroblasts and less than 10% were Tuj1+ committed neurons. These results demonstrate that the majority of cells die prior to becoming neurons and that Mcl-1 is required for their survival during this transition. In contrast to the apoptosis of Mcl-1 deficient neural progenitors, deletion of Mcl-1 in cultured neurons does not trigger an apoptotic response.
Discussion: Taken together, the results of our studies provide the first demonstration of a requirement for the anti-apoptotic Bcl-2 family protein, Mcl-1, in neuronal development and implicate Mcl-1 as a prime therapeutic target for the protection of neural precursors from apoptosis.
Acknowledgements: This work was supported by a grant from the Heart and Stroke Foundation of Ontario (HSFO) to RSS and a career transition award from the Canadian Stem Cell Network to JLV. NA, AJ, ECCC are supported by CIHR studentships, NL is supported by a HSFO studentship, MAK is supported by a HSFO postdoctoral fellowship.
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