Endothelin B receptor deficiency is associated with an increased rate of neuronal apoptosis in the dentate gyrus

Ehrenreich, Hannelore; Nau, Roland; Dembowski, Christoph; Hasselblatt, Martin; Barth, Martin; Hahn, Alfred W.A.; Schilling, Lothar; Sirén, Anna‐Leena; Brück, Wolfgang

doi:10.1016/s0306-4522(99)00507-2

Cited by 56 publications

(50 citation statements)

References 40 publications

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“…The expression of a constitutively active mutant of G␣q, G␣qR183C, inhibited cell migration, as did ET-1. Ehrendreih et al (35) reported that ETB receptor deficiency increased neuronal apoptosis in the dentate gyrus. However, no prominent phenotype has been reported in ET-1 knockout (36) or inducible ETB knockout (11) in cortical morphogenesis.…”

Section: Discussionmentioning

confidence: 99%

G protein-coupled receptor signaling through Gq and JNK negatively regulates neural progenitor cell migration

Mizuno

Kokubu

Sato

et al. 2005

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

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Section: Discussionmentioning

confidence: 99%

G protein-coupled receptor signaling through Gq and JNK negatively regulates neural progenitor cell migration

Mizuno

Kokubu

Sato

et al. 2005

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

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“…The +/sl and +/+ rats had a pigmented hood and back, without intestinal obstruction. The rats were genotyped by polymerase chain reaction as reported previously (Ceccherini et al 1995;Ehrenreich et al 2000). All treatment and experiments on animals were approved by animal ethics committee of the institution.…”

Section: Animalsmentioning

confidence: 99%

Deficiency in Endothelin Receptor B Reduces Proliferation of Neuronal Progenitors and Increases Apoptosis in Postnatal Rat Cerebellum

et al. 2008

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Endothelins regulate cellular functions in the mammalian brain through the endothelin receptors A and B (EDNRA and EDNRB). In this study, we investigated the role of EDNRB on cell proliferation in the cerebellum by using the spotting lethal (sl) rat, which carries a naturally occurring deletion in the EDNRB gene. Proliferating cells in the three genotypes, wild-type (+/+), heterozygous (+/sl) and homozygous mutant (sl/sl) rats were labelled by intraperitoneal injection of 5-bromo-2'-deoxyuridine (BrdU) at postnatal day 2. The density of BrdU-positive cells (per mm(2)) in the external germinal layer of sl/sl rats (Mean +/- SEM, 977 +/- 388) was significantly reduced compared to +/+ (4915 +/- 631) and +/sl (2304 +/- 557) rats. Subsequently, we examined the effects of EDNRB mutation on neural apoptosis by terminal deoxynucleotidyltransferase-mediated dUTP nick end-labelling assay. This showed that the density of apoptotic cells in the cerebella of sl/sl rats (9.3 +/- 0.5/mm(2)) was significantly more increased than +/+ rats (4 +/- 0.7). The expression of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) were measured with standard ELISA, but were unchanged in all genotypes. These results suggest that ENDRB mediates neural proliferation and have anti-apoptotic effects in the cerebellum of the postnatal rat, and that these effects are independent of changes in the expression of BDNF and GDNF. Our findings will lead to better understanding of the morphological changes in the cerebellum of Hirschsprung's disease patients with congenital EDNRB mutation.

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“…In the developing brain, ETB-receptor stimulation enhances proliferation and survival of the neural progenitor cells through a G i -protein coupled increase in phosphorylation of extracellular signal regulated kinases (ERKs) (6). Accordingly, lack of functional ETB-receptors in the spotting-lethal (sl/sl) rats leads to increased neuronal apoptosis in the dentate gyrus, a brain area known to harbor progenitor cells (4,8). The increased neuronal apoptosis in the ETB-deficient rats must be at least partially compensated by other systems, however, as the overall brain morphology of these rats is not altered (4,(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

“…It is now well established that endothelins through actions on their G-protein-coupled endothelin B(ETB)-receptors have effects on neuronal proliferation, survival and differentiation (2)(3)(4)(5)(6)(7). ETB-receptor agonists mediate anti-apoptotic actions in rat cortical neurons (5,7).…”

Section: Introductionmentioning

confidence: 99%

Hippocampal Cannabinoid-1 Receptor Upregulation Upon Endothelin-B Receptor Deficiency: A Neuroprotective Substitution Effect?

et al. 2005

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Endothelin (ETB)-receptors mediate anti-apoptotic actions. Lack of functional ETB-receptors leads to increased neuronal apoptosis in the hippocampus. The increased apoptosis must be compensated by other mechanisms, however, as ETB-deficient rats display normal overall brain morphology. To illuminate on brain plasticity in ETB-receptor deficiency, we studied the expression and function of another neuroprotective system, the cannabinoid CB1-receptors, in ETB-deficient hippocampus. We show that CB1 expression in hippocampus increases postnatally in all rats but that the increase in CB1-receptor expression is significantly higher in ETB-deficient compared to wildtype littermates. Neuronal apoptosis decreases during brain maturation but remains on a significantly higher level in the ETB-deficient compared to wildtype dentate. When investigating survival of hippocampal neurons in culture, we found significant protection against hypoxia-induced cell death with CB1-analogs (noladin, (9-tetrahydrocannabinol) only in ETB-deficient neurons. We suggest that CB1-receptor upregulation in the ETB-mutant hippocampus reflects an attempt to compensate for the lack of ETB-receptors.

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Endothelin B receptor deficiency is associated with an increased rate of neuronal apoptosis in the dentate gyrus

Cited by 56 publications

References 40 publications

G protein-coupled receptor signaling through Gq and JNK negatively regulates neural progenitor cell migration

G protein-coupled receptor signaling through Gq and JNK negatively regulates neural progenitor cell migration

Deficiency in Endothelin Receptor B Reduces Proliferation of Neuronal Progenitors and Increases Apoptosis in Postnatal Rat Cerebellum

Hippocampal Cannabinoid-1 Receptor Upregulation Upon Endothelin-B Receptor Deficiency: A Neuroprotective Substitution Effect?

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