mnd2: A New Mouse Model of Inherited Motor Neuron Disease

Jones, Julie Miller; Albin, Roger L.; Feldman, Eva L.; Simin, Karl; Schuster, Timothy G.; Dunnick, Wesley A.; Collins, John T.; Chrisp, Clarence E.; Taylor, Benjamin A.; Meisler, Miriam H.

doi:10.1006/geno.1993.1246

Cited by 66 publications

(57 citation statements)

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“…While overexpression of Smac/DIABLO or HtrA2/Omi certainly promotes caspase-mediated apoptotic death and also, in the case of HtrA2/Omi, caspase-independent cell death, the significance of the endogenous proteins in these pathways has been much less clear. The data presented here indicate that the complete loss of expression of HtrA2/Omi protein, along with its Reaper motif, does not obviously perturb mouse development and health beyond the effects seen due to the loss resulting from a point mutation of only the serine protease activity of HtrA2/Omi: the phenotype of the HtrA2/Omi knockout mouse is very similar to that of the Mnd2 mouse (11,12,21). Similarly, a total loss of Smac/DIABLO expression has no effect on mouse development or function (19).…”

Section: Discussionmentioning

confidence: 72%

Neuroprotective Role of the Reaper-Related Serine Protease HtrA2/Omi Revealed by Targeted Deletion in Mice

Martins

Morrison

Klupsch

et al. 2004

Molecular and Cellular Biology

361

319

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The serine protease HtrA2/Omi is released from the mitochondrial intermembrane space following apoptotic stimuli. Once in the cytosol, HtrA2/Omi has been implicated in promoting cell death by binding to inhibitor of apoptosis proteins (IAPs) via its amino-terminal Reaper-related motif, thus inducing caspase activity, and also in mediating caspase-independent death through its own protease activity. We report here the phenotype of mice entirely lacking expression of HtrA2/Omi due to targeted deletion of its gene, Prss25. These animals, or cells derived from them, show no evidence of reduced rates of cell death but on the contrary suffer loss of a population of neurons in the striatum, resulting in a neurodegenerative disorder with a parkinsonian phenotype that leads to death of the mice around 30 days after birth. The phenotype of these mice suggests that it is the protease function of this protein and not its IAP binding motif that is critical. This conclusion is reinforced by the finding that simultaneous deletion of the other major IAP binding protein, Smac/DIABLO, does not obviously alter the phenotype of HtrA2/Omi knockout mice or cells derived from them. Mammalian HtrA2/Omi is therefore likely to function in vivo in a manner similar to that of its bacterial homologues DegS and DegP, which are involved in protection against cell stress, and not like the proapoptotic Reaper family proteins in Drosophila melanogaster.

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Section: Discussionmentioning

confidence: 72%

Neuroprotective Role of the Reaper-Related Serine Protease HtrA2/Omi Revealed by Targeted Deletion in Mice

Martins

Morrison

Klupsch

et al. 2004

Molecular and Cellular Biology

361

319

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“…Because this region contains three disease loci with neurological phenotypes, i.e., truncate (41), mnd2 (42), and cerebellar deficient folia (43), we mapped the location of mouse Semaw by using a mouse͞hamster radiation hybrid panel to determine its location within the region accurately. This mapping placed Semaw between microsatellite markers D6Mit71 and D6Mit9 on chromosome 6, localizing the gene to approximately the same position as the mnd2 locus (ref.…”

Section: Resultsmentioning

confidence: 99%

Cloning, expression, and genetic mapping of Sema W, a member of the semaphorin family

Encinas

Kikuchi

Chédotal

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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The semaphorins comprise a large family of membrane-bound and secreted proteins, some of which have been shown to function in axon guidance. We have cloned a transmembrane semaphorin, Sema W, that belongs to the class IV subgroup of the semaphorin family. The mouse and rat forms of Sema W show 97% amino acid sequence identity with each other, and each shows about 91% identity with the human form. The gene for Sema W is divided into 15 exons, up to 4 of which are absent in the human cDNAs that we sequenced. Unlike many other semaphorins, Sema W is expressed at low levels in the developing embryo but was found to be expressed at high levels in the adult central nervous system and lung. Functional studies with purified membrane fractions from COS7 cells transfected with a Sema W expression plasmid showed that Sema W has growth-cone collapse activity against retinal ganglion-cell axons, indicating that vertebrate transmembrane semaphorins, like secreted semaphorins, can collapse growth cones. Genetic mapping of human SEMAW with human͞hamster radiation hybrids localized the gene to chromosome 2p13. Genetic mapping of mouse Semaw with mouse͞hamster radiation hybrids localized the gene to chromosome 6, and physical mapping placed the gene on bacteria artificial chromosomes carrying microsatellite markers D6Mit70 and D6Mit189. This localization places Semaw within the locus for motor neuron degeneration 2, making it an attractive candidate gene for this disease.Development of the nervous system requires that axonal projections reach the correct targets. Within the last few years, a number of molecules have been found that have the ability to guide axonal growth by providing a repulsive signal that inhibits axons from straying outside of their correct paths. Most of these repellant molecules identified to date belong to the semaphorin family. In vitro, semaphorin family members collapsin 1 (1) and Sema D (2) can repel axons and cause growth-cone collapse. In vivo, grasshopper and Drosophila Sema I (3, 4) and Drosophila Sema II (5) can influence axon trajectories, and targeted disruption of the gene for Sema D, or its receptor neuropilin 1, leads to severe abnormalities in peripheral nerve projection (6, 7). Recently, new members of the semaphorin family have been described that have effects outside of the nervous system. Human CD100, known as Sema J in the mouse, has been found to function in T cell and B cell aggregation and activation (8, 9). Human Sema E has been found to be involved in the resistance of cancers to radiation and chemotherapeutic drugs (10), and mouse Sema H expression has been found to correlate with the metastatic ability of tumor cell lines (11). In addition, two viral genes bearing significant homology to semaphorin have been described in alcelaphine herpesvirus 1 and vaccinia virus, although the function of these genes is not yet known.In mammals, 15 members of the semaphorin family of molecules have been described to date and, together with avian and insect semaphorins, can be grouped int...

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“…This was suggested by the identification of a single mutation in the Omi gene as the cause of the mnd2 phenotype in mice (9,20). This mutation inactivates the proteolytic activity of Omi without affecting its protein level or subcellular localization.…”

Section: Discussionmentioning

confidence: 99%

Regulation of HAX-1 Anti-apoptotic Protein by Omi/HtrA2 Protease during Cell Death

Cilenti

Soundarapandian

Kyriazis

et al. 2004

Journal of Biological Chemistry

165

141

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Omi/HtrA2 is a nuclear-encoded mitochondrial serine protease that has a pro-apoptotic function in mammalian cells. Upon induction of apoptosis, Omi translocates to the cytoplasm and participates in caspase-dependent apoptosis by binding and degrading inhibitor of apoptosis proteins. Omi can also initiate caspase-independent apoptosis in a process that relies entirely on its ability to function as an active protease. To investigate the mechanism of Omi-induced apoptosis, we set out to isolate novel substrates that are cleaved by this protease. We identified HS1-associated protein X-1 (HAX-1), a mitochondrial anti-apoptotic protein, as a specific Omi interactor that is cleaved by Omi both in vitro and in vivo. HAX-1 degradation follows Omi activation in cells treated with various apoptotic stimuli. Using a specific inhibitor of Omi, HAX-1 degradation is prevented and cell death is reduced. Cleavage of HAX-1 was not observed in a cell line derived from motor neuron degeneration 2 mice that carry a mutated form of Omi that affects its proteolytic activity. Degradation of HAX-1 is an early event in the apoptotic process and occurs while Omi is still confined in the mitochondria. Our results suggest that Omi has a unique pro-apoptotic function in mitochondria that involves removal of the HAX-1 antiapoptotic protein. This function is distinct from its ability to activate caspase-dependent apoptosis in the cytoplasm by degrading inhibitor of apoptosis proteins.Omi/HtrA2 is a mitochondrial serine protease that is released to the cytoplasm upon induction of apoptosis (1-4). In the cytoplasm, Omi binds and cleaves IAPs 1 leading to activation of caspase-dependent apoptosis (5, 6). Omi can also induce caspase-independent apoptosis through an as yet unknown mechanism that requires its proteolytic activity (7,8). In addition to its pro-apoptotic function, Omi has another unique role in maintaining mitochondrial homeostasis, but the details of this mechanism are still unclear (9). The serine protease activity of Omi is necessary and essential for its normal function whether it acts as a pro-apoptotic protein in the cytoplasm or as a potential chaperone in the mitochondria (9). The proteolytic activity of Omi has been associated with autoprocessing to form the mature protein as well as cleavage of IAPs to activate caspase-dependent apoptosis (5,6,8). To understand the mechanism of Omi's function, it will be necessary to identify new substrates for this protease. These substrates might be mitochondrial or cytoplasmic proteins, and their degradation and removal by Omi could be part of the apoptotic process. In this report, we used the yeast two-hybrid system to isolate and characterize new Omi-interacting proteins. One of these interactors isolated from this screen was the HS1-associated protein X-1 (HAX-1) anti-apoptotic protein (10). HAX-1 interacted with Omi both in vitro and in vivo. Furthermore, HAX-1 was degraded and removed by Omi when cells were treated with various apoptotic stimuli. Using a specific inhibitor of the pro...

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mnd2: A New Mouse Model of Inherited Motor Neuron Disease

Cited by 66 publications

References 0 publications

Neuroprotective Role of the Reaper-Related Serine Protease HtrA2/Omi Revealed by Targeted Deletion in Mice

Neuroprotective Role of the Reaper-Related Serine Protease HtrA2/Omi Revealed by Targeted Deletion in Mice

Cloning, expression, and genetic mapping of Sema W, a member of the semaphorin family

Regulation of HAX-1 Anti-apoptotic Protein by Omi/HtrA2 Protease during Cell Death

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