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

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Abstract

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 mm2) 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/mm2) 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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Acknowledgements

This study was partly supported by the Canberra Hospital Private Practice Fund and the ACT Government.

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Authors and Affiliations

  1. Division of Neuroscience, John Curtin School of Medical Research, Australian National University, Building 54, Garran Road, Canberra, ACT, 0200, Australia

    Maria Vidovic, Ming-Ming Chen, Qun-Ying Lu, Abel H. Y. Tan & Zan-Min Song

  2. Medical School, Australian National University, Canberra, ACT, Australia

    Katherine F. Kalloniatis, Ben M. Martin & Zan-Min Song

  3. Paediatric Surgery, The Canberra Hospital, Canberra, ACT, Australia

    Celina Lynch & G. David H. Croaker

  4. Children’s Hospital at Westmead, Sydney, NSW, Australia

    Daniel T. Cass

  5. Department of Gynecology and Obstetrics, the First Affiliated Hospital, Kunming Medical College, Yunan, China

    Qun-Ying Lu

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  1. Maria Vidovic
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Correspondence to Zan-Min Song.

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Vidovic, M., Chen, MM., Lu, QY. et al. Deficiency in Endothelin Receptor B Reduces Proliferation of Neuronal Progenitors and Increases Apoptosis in Postnatal Rat Cerebellum. Cell Mol Neurobiol 28, 1129–1138 (2008). https://doi.org/10.1007/s10571-008-9292-z

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