Critical role for DP5/Harakiri, a Bcl-2 homology domain 3-only Bcl-2 family member, in axotomy-induced neuronal cell death.
نویسندگان
چکیده
The survival of neurons is maintained primarily by neurotrophic factors that suppress the apoptotic program. Axotomy or removal of peripheral targets causes neuronal cell death, but the mechanisms involved in the induction of this type of cell death remain poorly understood. Here, we show that DP5/Harakiri, a Bcl-2 homology domain 3-only member of the Bcl-2 family, is induced in motoneurons after transection of the hypoglossal nerve in mice and in sympathetic neurons after nerve growth factor (NGF) withdrawal. To assess the role of DP5 in neuronal cell death, mutant mice deficient in DP5 were generated by gene targeting. DP5-/- mice were viable and exhibited normal postnatal development. Notably, motoneurons from DP5-/- mice were highly protected from cell death induced by resection of the hypoglossal nerve compared with motoneurons from DP5+/+ littermate mice. In addition, deficiency of DP5 in superior cervical ganglia (SCG) neurons resulted in delayed neuronal cell death triggered by NGF withdrawal. Analysis of SCG neurons from DP5-/- mice revealed increased preservation of mitochondrial membrane potential and reduced activation of caspase-3 compared with neurons from wild-type mice. These results indicate that DP5 plays an important role in neuronal cell death induced by axotomy and NGF deprivation through the regulation of mitochondrial function and caspase-3 activation.
منابع مشابه
A Convoluted Way to Die
velopment is initiated by transcriptional upregulation of Ivelisse Sánchez and Junying Yuan* Egl-1, another BH3-only member of the BCL-2 family Department of Cell Biology that acts by inhibiting Ced-9, an antiapoptotic member Harvard Medical School of the BCL-2 family (Conradt and Horvitz, 1998). 240 Longwood Avenue BIM may not be the only BH3-only member that is Boston, Massachusetts 02115 ind...
متن کاملThe proapoptotic BCL-2 homology domain 3-only protein Bim is not critical for acute excitotoxic cell death.
Prolonged and repetitive epileptic activity is causally linked to neuronal cell death in the brain and is most marked in vulnerable subfields of the hippocampus. The Bcl-2 family protein Bim, a proapoptotic member of the BCL-2 homology domain 3-only subfamily, has been implicated as an important mediator of neuronal cell damage in various pathological conditions, although its role in epilepsy-a...
متن کاملIntrinsic Order and Disorder in the Bcl-2 Member Harakiri: Insights into Its Proapoptotic Activity
Harakiri is a BH3-only member of the Bcl-2 family that localizes in membranes and induces cell death by binding to prosurvival Bcl-x(L) and Bcl-2. The cytosolic domain of Harakiri is largely disorder with residual α-helical conformation according to previous structural studies. As these helical structures could play an important role in Harakiri's function, we have used NMR and circular dichroi...
متن کاملThe C. elegans Protein EGL-1 Is Required for Programmed Cell Death and Interacts with the Bcl-2–like Protein CED-9
Gain-of-function mutations in the Caenorhabditis elegans gene egl-1 cause the HSN neurons to undergo programmed cell death. By contrast, a loss-of-function egl-1 mutation prevents most if not all somatic programmed cell deaths. The egl-1 gene negatively regulates the ced-9 gene, which protects against cell death and is a member of the bcl-2 family. The EGL-1 protein contains a nine amino acid r...
متن کاملBcl-rambo, a novel Bcl-2 homologue that induces apoptosis via its unique C-terminal extension.
The Bcl-2 family of proteins plays a central regulatory role in apoptosis. We have identified a novel, widely expressed Bcl-2 member which we have named Bcl-rambo. Bcl-rambo shows overall structural homology to the anti-apoptotic Bcl-2 members containing conserved Bcl-2 homology (BH) motifs 1, 2, 3, and 4. Unlike Bcl-2, however, the C-terminal membrane anchor region is preceded by a unique 250 ...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- The Journal of neuroscience : the official journal of the Society for Neuroscience
دوره 24 15 شماره
صفحات -
تاریخ انتشار 2004