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ABSTRACT: Malignant progression of choroid plexus papillomas has been occasionally reported, but this issue has not yet been systematically addressed.
Frequency and extent of malignant progression were examined in a retrospective series of 124 primary choroid plexus papillomas using uniform histological criteria.
After gross-total resection and a mean follow-up period of 59 months, 12 recurrences necessitating neurosurgical intervention had occurred in the 103 cases of choroid plexus papilloma (World Health Organization [WHO] Grade I) and 21 cases of atypical choroid plexus papilloma (WHO Grade II). The proportion of recurring tumors was higher in cases of atypical choroid plexus papilloma than in cases of choroid plexus papilloma (six [29%] of 21 compared with six [6%] of 103, respectively; p < 0.05). In the majority (10 of 12) of the recurrences, there was a close correspondence between the primary tumor and the recurrence with respect to features identified on routine histological examination as well as Ki 67 (MIB-1) proliferation indices (median value 4% for both primary and recurrent tumors; range 0-15% for primary compared with 0-12% for recurrent tumors). However, two patients experienced a transition from a choroid plexus papilloma (WHO Grade I) and an atypical choroid plexus papilloma (WHO Grade II) to choroid plexus carcinomas (WHO Grade III).
Recurrent tumor growth after gross-total resection is rare in choroid plexus papillomas, but malignant progression to choroid plexus carcinoma does occur in a small percentage of tumors.
Journal of Neurosurgery 09/2007; 107(3 Suppl):199-202. · 2.96 Impact Factor
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ABSTRACT: Granulocyte-colony stimulating factor (G-CSF) receptor signaling counteracts detrimental pathways in ischemic stroke. In rodents, neuroprotection provided by the G-CSF system involves up-regulation of the G-CSF receptor and its ligand, G-CSF, during cerebral ischemia. The confirmation of a similar response in the human brain would be an important rationale for the use of G-CSF in clinical stroke trials. Therefore, the temporal and cellular profile of G-CSF and G-CSF receptor expression was examined in a series of human stroke brains. The median age of the 21 stroke patients was 67 years; median time from death to autopsy was 24 h (range: 10-67 h). In acute ischemic stroke, strong neuronal G-CSF receptor immunoreactivity was encountered in the infarct area and the peri-infarct rim as compared to the contralateral cortex. In subacute infarctions, microglial and macrophage G-CSF receptor immunoreactivity predominated, whereas chronic infarction was characterized by the presence of G-CSF receptor expressing reactive astrocytes. Neuronal G-CSF expression was encountered very early upon ischemic stroke. At later time-points, an up-regulation of vascular G-CSF expression in the peri-infarct area prevailed. In conclusion, the observed up-regulation of G-CSF receptors and G-CSF points towards a role in the pathophysiology of human ischemic stroke.
Acta Neuropathologica 02/2007; 113(1):45-51. · 9.32 Impact Factor
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ABSTRACT: The prognostic significance of atypical histologic features in choroid plexus tumors remains uncertain. Therefore, a series of 164 choroid plexus tumors was evaluated for the presence of atypical histologic features, including mitotic activity, increased cellularity, nuclear pleomorphism, blurring of papillary growth pattern, and necrosis. The impact of histopathologic and clinical features on the probability of recurrence and survival was investigated. Twenty-four tumors displaying frank signs of malignancy were diagnosed as choroid plexus carcinoma according to World Health Organization criteria. Of 124 choroid plexus papillomas that had not received adjuvant treatment, 46 tumors (37%) displayed at least one atypical feature, including increased cellularity (n = 25 [20%]), mitotic activity (> or =2 mitoses per 10 high-power fields; n = 19 [15%]), nuclear pleomorphism (n = 16 [13%]), solid growth (n = 15 [12%]), and necrosis (n = 5 [4%]). Only one tumor-related death, but 10 recurrences, were observed on a mean observation time of 58 months. On univariate analysis, incomplete surgical resection (p = 0.03) and mitotic activity (p < 0.001) were the only clinicopathologic factors associated with recurrence. Using a multivariate model, an independent effect of mitotic activity on the probability of recurrence could be confirmed (p = 0.001). Because mitotic activity is the sole atypical histologic feature independently associated with recurrence, we propose to define atypical choroid plexus papilloma by mitotic activity (> or =2 mitoses per 10 high-power fields) corresponding to World Health Organization grade II, thus adjoining other intermediate tumor entities associated with increased mitotic activity such as atypical meningioma. Close follow up of patients harboring atypical choroid plexus papillomas may be warranted.
Journal of Neuropathology and Experimental Neurology 12/2006; 65(11):1069-73. · 4.26 Impact Factor
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Michelle Fèvre-Montange, Martin Hasselblatt,
Dominique Figarella-Branger,
Laurent Chauveinc,
Jacques Champier,
Ghislaine Saint-Pierre,
Luc Taillandier,
Alix Coulon,
Werner Paulus,
François Fauchon,
Anne Jouvet
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ABSTRACT: Papillary tumor of the pineal region (PTPR) is a recently described tumor entity thought to arise from the specialized ependyma of the subcommissural organ. Whereas histologic features of PTPR are well defined, data on the prognostic value of PTPR remain scarce. We therefore investigated clinicopathologic features, including data on progression-free survival and overall survival, in a retrospective series of 31 PTPR. The age of the 14 males and 17 females ranged from 5 to 66 years (median age, 29 years). Histologically, all tumors were characterized by an epithelial-like growth pattern in which the vessels were covered by layers of columnar or cuboidal tumor cells forming perivascular pseudorosettes. Most of the tumor cells showed strong expression of neuron-specific enolase, cytokeratins (particularly CK18), S-100 protein, and vimentin. Most PTPRs examined also expressed microtubule-associated protein-2. Expression of synaptophysin, epithelial membrane antigen, transthyretin, neural cell adhesion molecule, and nestin was encountered in some tumors. Gross total resection could be achieved in 21 of 31 cases; 15 patients received radiotherapy on resection of the primary tumor. Nevertheless, the majority of patients experienced recurrences; 5-year estimates for overall survival and progression-free survival were 73% and 27%, respectively. To conclude, the clinical course of PTPR is characterized by frequent local recurrence, and the value of radiotherapy on disease progression will need to be investigated in future prospective trials.
Journal of Neuropathology and Experimental Neurology 11/2006; 65(10):1004-11. · 4.26 Impact Factor
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ABSTRACT: Capillary hemangioblastomas of the central nervous system are benign tumors and occur either sporadically or as a manifestation of von Hippel-Lindau disease. A rarer cellular and a more common reticular variant can be distinguished on the basis of the abundance of the stromal cell component, with the cellular variant being significantly associated with a greater probability of recurrence. To investigate whether these subtypes differ in their cytogenetic profile, a comparative genomic hybridization analysis of 10 cellular and 10 reticular hemangioblastomas was undertaken. Comparative genomic hybridization revealed DNA copy number changes in 14 of 20 cases (8 of 10 cellular and 6 of 10 reticular hemangioblastomas). The most common changes overall were losses of chromosomes 19 (35%), 6 (30%), and 22q (15%), whereas loss of 3 and gain of 4 were encountered in one case each (5%). The cellular variant showed losses of chromosomes 6 (60%), 22q and 19 (20% each), as well as gain of 4 (10%), whereas the reticular variant presented with losses of chromosomes 19 (50%), 22q and 3 (10% each). Loss of chromosome 6 was significantly associated with the cellular subtype (P < .005), whereas loss of 19/19p was found more frequently in the reticular variant, albeit not significantly (P = .16). In conclusion, our data may point toward different genetic pathways in the pathogenesis of the 2 histologic subtypes of capillary hemangioblastoma.
Human Pathlogy 11/2006; 37(11):1452-7. · 2.88 Impact Factor
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Acta Neuropathologica 11/2006; 112(4):513-4. · 9.32 Impact Factor
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Karla Punkt,
Stefan Schering,
Sabine Löffler,
Evgeny A Minin,
Vera E Samoilova, Martin Hasselblatt,
Werner Paulus,
Ursula Müller-Werdan,
Uta Demus,
Gabriele Koehler,
Werner Boecker,
Igor B Buchwalow
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ABSTRACT: Nitric oxide (NO) mediates fundamental physiological actions on skeletal muscle. The neuronal NO synthase isoform (NOS1) was reported to be located exclusively in the sarcolemma. Its loss from the sarcolemma was associated with development of Duchenne muscular dystrophy (DMD). However, new studies evidence that all three NOS isoforms-NOS1, NOS2, and NOS3-are co-expressed in the sarcoplasm both in normal and in DMD skeletal muscles. To address this controversy, we assayed NOS expression in DMD myofibers in situ cytophotometrically and found NOS expression in DMD myofibers up-regulated. These results support the hypothesis that NO deficiency with consequent muscle degeneration in DMD results from NO scavenging by superoxides rather than from reduced NOS expression.
Biochemical and Biophysical Research Communications 10/2006; 348(1):259-64. · 2.48 Impact Factor
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ABSTRACT: Rhabdoid tumors represent an independent entity among embryonal neoplasms. These tumors affect the kidney (RTK, rhabdoid tumor of kidney) and central nervous system (AT/RT, atypical teratoid, rhabdoid tumor), but may also be found in peripheral soft tissue. Unifying features include immunohistochemical characteristics and inactivation of the putative tumor suppressor gene SMARCB1 (hSNF5/INI1) in chromosome 22q11.2. Several familial cases have been published and summarized under the term rhabdoid tumor predisposition syndrome. In all of the published familial cases, inactivation of SMARCB1 was detected in tumor tissues.
We report on a family with three children, two of which were affected by rhabdoid tumors, one RTK, the other an AT/RT. While both children demonstrated typical morphological and clinical features neither the RTK nor the AT/RT showed evidence for inactivation of SMARCB1 in molecular studies including CGH and array CGH, FISH, gene dosage analysis by dHPLC, and DNA-sequencing. Immunohistochemistry for SMARCB1 showed normal expression within the nuclei of tumor cells. Furthermore, both children inherited different paternal and maternal SMARCB1 alleles evidenced by haplotype analysis. Conventional cytogenetic, FISH, and mutation analyses lacked evidence for SMARCB1 aberrations or gross chromosomal changes in the parents.
We thus demonstrate a family with rhabdoid tumor predisposition syndrome without linkage to SMARCB1. This finding indicates that other loci than SMARCB1 below the resolution of array CGH are involved in the origin of these tumors. Our data impact on the clinical counseling of affected families and warrant further studies in the molecular biology of these enigmatic tumors.
Pediatric Blood & Cancer 10/2006; 47(3):273-8. · 1.89 Impact Factor
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Igor B Buchwalow,
Evgeny A Minin,
Frank-Ulrich Müller,
Geertje Lewin,
Vera E Samoilova,
Wilhelm Schmitz,
Maren Wellner, Martin Hasselblatt,
Karla Punkt,
Ursula Müller-Werdan,
Uta Demus,
Jan Slezak,
Gabriele Koehler,
Werner Boecker
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ABSTRACT: Duchenne and Becker muscular dystrophies (DMD and BMD) are associated with decreased total nitric oxide (NO). However, mechanisms leading to NO deficiency with consequent muscle-cell degeneration remain unknown. To address this issue, we examined skeletal muscles of DMD and BMD patients for co-expression of NO synthase (NOS) with nitrotyrosine and transcription factor CREB, as well as with enzymes engaged in NO signaling. Employing immunocytochemical labeling, Western blotting and RT-PCR, we found that, in contrast to the most commonly accepted view, neuronal NOS was not restricted to the sarcolemma and that muscles of DMD and BMD patients retained all three NOS isoforms with an up-regulation of the inducible NOS isoform, CREB and nitrotyrosine. We suggest that enhanced nitrotyrosine immunostaining in muscle fibers as well as in the vasculature of DMD and BMD specimens reflects massive oxidative stress, resulting in withdrawal of NO from its regular physiological course via the scavenging actions of superoxides.
Acta Neuropathologica 07/2006; 111(6):579-88. · 9.32 Impact Factor
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ABSTRACT: Ependymoblastomas are very rare and highly malignant embryonal tumours of the central nervous system with distinctive multilayered rosettes being the main histopathological feature. They are a diagnostically challenging subtype of embryonal tumours, whose genetic features are unknown. Primary ependymoblastomas from four children (one boy, three girls; mean age 24.8 months, range 4-41 months) were investigated by comparative genomic hybridisation (CGH), to our knowledge constituting the only cohort of this entity studied by cytogenetic means. DNA copy number changes were found in each case, consisting mainly of gains of chromosome 2 as well as losses of chromosomes 6q and 13q (75% each). The tumours showed between one and five aberrations with a mean of 3.25 DNA copy number changes per case, with gains being less frequent than losses (1.25 gains vs 2 losses per case). The youngest patient showed the least imbalances (one), whereas the oldest child presented with the most aberrations (five). Clinical follow-up data were available for three of the four patients. All three had died of their disease after a post-operative survival of 9 months (range 6-14 months). Our CGH data suggest that ependymoblastomas show distinct and fairly consistent chromosomal aberrations.
Acta Neuropathologica 07/2006; 111(6):559-62. · 9.32 Impact Factor
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ABSTRACT: Ependymoblastomas are very rare and highly malignant embryonal tumours of the central nervous system with distinctive multilayered rosettes being the main histopathological feature. They are a diagnostically challenging subtype of embryonal tumours, whose genetic features are unknown. Primary ependymoblastomas from four children (one boy, three girls; mean age 24.8 months, range 4-41 months) were investigated by comparative genomic hybridisation (CGH), to our knowledge constituting the only cohort of this entity studied by cytogenetic means. DNA copy number changes were found in each case, consisting mainly of gains of chromosome 2 as well as losses of chromosomes 6q and 13q (75% each). The tumours showed between one and five aberrations with a mean of 3.25 DNA copy number changes per case, with gains being less frequent than losses (1.25 gains vs 2 losses per case). The youngest patient showed the least imbalances (one), whereas the oldest child presented with the most aberrations (five). Clinical follow-up data were available for three of the four patients. All three had died of their disease after a post-operative survival of 9 months (range 6-14 months). Our CGH data suggest that ependymoblastomas show distinct and fairly consistent chromosomal aberrations.
Acta Neuropathologica 06/2006; · 9.32 Impact Factor
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ABSTRACT: The discovery of the broad neuroprotective potential of erythropoietin (EPO), an endogenous hematopoietic growth factor, has opened new therapeutic avenues in the treatment of brain diseases. EPO expression in the brain is induced by hypoxia. Practically all brain cells are capable of production and release of EPO and expression of its receptor. EPO exerts multifaceted protective effects on brain cells. It protects neuronal cells from noxious stimuli such as hypoxia, excess glutamate, serum deprivation or kainic acid exposure in vitro by targeting a variety of mechanisms and involves neuronal, glial and endothelial cell functions. In rodent models of ischemic stroke, EPO reduces infarct volume and improves functional outcome, but beneficial effects have also been observed in animal models of subarachnoid hemorrhage, intracerebral hemorrhage, traumatic brain injury, and spinal cord injury. EPO has a convenient therapeutic window upon ischemic stroke and favorable pharmacokinetics. Results from first therapeutic trials in humans are promising, but will need to be validated in larger trials. The safety profile and effectiveness of EPO in a wide variety of neurologic disease models make EPO a candidate compound for a potential first-line therapeutic for neurologic emergencies.
Journal of Neurosurgical Anesthesiology 05/2006; 18(2):132-8. · 2.23 Impact Factor
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ABSTRACT: The value of routine histopathological examination of intervertebral disc tissue has been questioned, but sufficient numbers of studies have yet to be conducted to provide a definitive sense of its importance. The aim of this study was to investigate the nature and frequency of unexpected histopathological findings in intervertebral disc surgery.
The authors conducted a retrospective examination of consecutive surgical specimens obtained in patients with benign indication for discectomy at four neurosurgical centers. Surgical specimens obtained during 2102 operations (2177 intervertebral discs) in 2017 patients were evaluated. In addition to one case of cavernous malformation, two specimens (obtained in 0.1% of patients) revealed unexpected pathological diagnoses of malignancy (metastasized prostate carcinoma and diffuse large B-cell lymphoma).
The results of this retrospective study suggest that routine histopathological examination of specimens obtained during intervertebral disc procedures is both justified and cost effective.
Journal of Neurosurgery Spine 02/2006; 4(1):20-3. · 1.53 Impact Factor
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ABSTRACT: Astrocytes play a pivotal role in supporting neuronal survival. In order to better understand the contribution of astrocytes towards adaptive mechanisms, gene expression profiles were analyzed after exposure of primary rat astrocyte cultures to normoxic or hypoxic (<3% O2) conditions using high-density oligonucleotide microarrays and quantitative reverse transcriptase polymerase chain reaction. Twenty-five genes were more than 1.5 fold upregulated, whereas 12 genes were more than 1.5-fold downregulated upon hypoxia (P<0.05). Upregulation of established hypoxia-inducible factor 1 target genes as well as novel transcripts related to energy metabolism, astrocyte survival and differentiation, and lipoprotein binding was confirmed by quantitative reverse transcriptase polymerase chain reaction. Further analysis of these genes might provide a better understanding of astrocyte function upon hypoxic conditions.
Neuroreport 02/2006; 17(1):51-4. · 1.66 Impact Factor
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ABSTRACT: To identify specific markers for the diagnosis of choroid plexus tumors, gene expression profiles of choroid plexus epithelial cells (n = 8) and ependymal cells (n = 6) microdissected from human autopsy brains as well as choroid plexus papilloma tissue were investigated using DNA microarrays. Protein expression of genes overexpressed in choroid plexus was evaluated in normal choroid plexus, choroid plexus papilloma, choroid plexus carcinoma, other primary brain tumors, and cerebral metastases. Forty-six genes found to be overexpressed in normal choroid plexus epithelial cells were also present in choroid plexus papilloma. Among those, 11 were further analyzed by immunohistochemistry. Expression of inward rectifier potassium channel Kir7.1 was confirmed in normal choroid plexus (34 of 35), choroid plexus papilloma (12 of 18), and choroid plexus carcinoma (5 of 5) but was not found in 100 other primary brain tumors and cerebral metastases. Similarly, stanniocalcin-1 stained normal choroid plexus (32 of 35), choroid plexus papilloma (16 of 18), and choroid plexus carcinoma (3 of 5), whereas staining was seen in only 2 of 100 other primary brain tumors and cerebral metastases. Transthyretin stained choroid plexus (33 of 35), choroid plexus papilloma (14 of 18), and plexus carcinoma (2 of 5), but its specificity was significantly lower. Antibodies directed against coagulation factor V, glutathione peroxidase 3, pigment epithelium derived factor, serotonin receptor 5-HTR2C, lumican, fibulin-1, plastin-1, and cytokeratin 18 revealed varying degrees of specificity and sensitivity. Our data suggest that antibodies directed against Kir7.1 and stanniocalcin-1 might serve as sensitive and specific diagnostic markers for choroid plexus tumors.
American Journal of Surgical Pathology 02/2006; 30(1):66-74. · 4.35 Impact Factor
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Armin Schneider,
Carola Krüger,
Tobias Steigleder,
Daniela Weber,
Claudia Pitzer,
Rico Laage,
Jaroslaw Aronowski,
Martin H Maurer,
Nikolaus Gassler,
Walter Mier, Martin Hasselblatt,
Rainer Kollmar,
Stefan Schwab,
Clemens Sommer,
Alfred Bach,
Hans-Georg Kuhn,
Wolf-Rüdiger Schäbitz
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ABSTRACT: G-CSF is a potent hematopoietic factor that enhances survival and drives differentiation of myeloid lineage cells, resulting in the generation of neutrophilic granulocytes. Here, we show that G-CSF passes the intact blood-brain barrier and reduces infarct volume in 2 different rat models of acute stroke. G-CSF displays strong anti-apoptotic activity in mature neurons and activates multiple cell survival pathways. Both G-CSF and its receptor are widely expressed by neurons in the CNS, and their expression is induced by ischemia, which suggests an autocrine protective signaling mechanism. Surprisingly, the G-CSF receptor was also expressed by adult neural stem cells, and G-CSF induced neuronal differentiation in vitro. G-CSF markedly improved long-term behavioral outcome after cortical ischemia, while stimulating neural progenitor response in vivo, providing a link to functional recovery. Thus, G-CSF is an endogenous ligand in the CNS that has a dual activity beneficial both in counteracting acute neuronal degeneration and contributing to long-term plasticity after cerebral ischemia. We therefore propose G-CSF as a potential new drug for stroke and neurodegenerative diseases.
Journal of Clinical Investigation 09/2005; 115(8):2083-98. · 15.39 Impact Factor
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ABSTRACT: Juvenile psammomatoid ossifying fibroma (JPOF) is a benign fibroosseous lesion predominantly arising within the paranasal sinuses in children and young adults. Neurocranial occurrence is exceedingly rare and a location within the neurocranial portion of the temporal bone has not been described. The authors report on one case of sinonasal JPOF secondarily extending into the cranial cavity and three cases primarily affecting the neurocranial bones to increase clinical awareness of this uncommon tumor, which may be easily mistaken for meningioma. Moreover, the absence of activating missense mutations of the GNAS1 gene in two cases strongly argues against a relationship between JPOF and fibrous dysplasia.
Journal of Neurosurgery 07/2005; 102(6):1151-4. · 2.96 Impact Factor
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ABSTRACT: Gender differences in neuropsychiatric disease are recognized but not well understood. Investigating the survival of primary rat hippocampal neurons in culture, we found significant and inverted gender differences on normoxia versus hypoxia. Male cells were more resistant under normoxia but more vulnerable under hypoxia than female cells. Male vulnerability pattern was acquired in cells from neonatally testosterone-primed females. Estrogens, acting via membrane receptors, had a higher neuroprotective power in male neurons, explained at least in part by the pronounced increase in estrogen receptor beta/alpha ratio during hypoxia in male cells only.
Journal of Cerebral Blood Flow & Metabolism 05/2005; 25(4):427-30. · 5.01 Impact Factor
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ABSTRACT: Gender differences in neuropsychiatric disease are recognized but not well understood. Investigating the survival of primary rat hippocampal neurons in culture, we found significant and inverted gender differences on normoxia versus hypoxia. Male cells were more resistant under normoxia but more vulnerable under hypoxia than female cells. Male vulnerability pattern was acquired in cells from neonatally testosterone-primed females. Estrogens, acting via membrane receptors, had a higher neuroprotective power in male neurons, explained at least in part by the pronounced increase in estrogen receptor beta/alpha ratio during hypoxia in male cells only.Keywords: aromatase, estrogen receptor alpha, estrogen receptor beta, hippocampus, sex, testosterone
Journal of Cerebral Blood Flow & Metabolism 02/2005; 25(4):427-430. · 5.01 Impact Factor
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ABSTRACT: Central nervous and hematopoietic systems share developmental features. We report that thrombopoietin (TPO), a stimulator of platelet formation, acts in the brain as a counterpart of erythropoietin (EPO), a hematopoietic growth factor with neuroprotective properties. TPO is most prominent in postnatal brain, whereas EPO is abundant in embryonic brain and decreases postnatally. Upon hypoxia, EPO and its receptor are rapidly reexpressed, whereas neuronal TPO and its receptor are down-regulated. Unexpectedly, TPO is strongly proapoptotic in the brain, causing death of newly generated neurons through the Ras-extracellular signal-regulated kinase 1/2 pathway. This effect is not only inhibited by EPO but also by neurotrophins. We suggest that the proapoptotic function of TPO helps to select for neurons that have acquired target-derived neurotrophic support.
Proceedings of the National Academy of Sciences 02/2005; 102(3):862-7. · 9.68 Impact Factor
