title: Reduced cell proliferation and increased apoptosis in the hippocampal formation in a rat model of Hirschsprung's disease.
abstract: Hirschsprung's disease (HSCR) is a congenital malformation characterized by the absence of enteric ganglia in the distal intestine and gut obstruction. Some HSCR patients also have associated neurological symptoms. We studied a rat model of HSCR, also known as spotting lethal (sl/sl) rat, which carries a spontaneous deletion in the gene of endothelin receptor B (EDNRB) and a similar phenotype as humans with HSCR. We focused on the changes in cell proliferation and apoptosis in the hippocampal formation of the sl/sl rat. Proliferating cells in wildtype (+/+), heterozygous (+/sl) and homozygous (sl/sl) rats were labelled by intraperitoneal injection of 5-bromo-2'-deoxyuridine (BrdU) at postnatal day 2. The density of proliferating cells in the CA1 and CA3 regions of the hippocampus and dentate gyrus of sl/sl rats was significantly reduced compared to +/+ rats. The effect of EDNRB mutation on cell apoptosis was examined by using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling assay. This showed that the density of apoptotic cells in the hippocampal formation, particularly in the CA1 region of sl/sl rats, was significantly increased compared to +/+ rats. The expression of brain derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) was measured with ELISA in the hippocampal formation, but no difference was revealed between genotypes. These results suggest that EDNRB mutation reduces cell proliferation and increases apoptosis in the hippocampal formation of the sl/sl rat, but does not alter the levels of BDNF and GDNF. Our findings provide an insight into the cellular changes in the brains of HSCR patients caused by EDNRB mutation.
authors.affiliation: Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Eccles Institute of Neuroscience, John Curtin School of Medical Research, the Australian National University, Canberra, ACT, Australia.
authors.forename: Dan
authors.initials: D
authors.lastname: Xie
authors.affiliation: Department of Paediatric Surgery, The Canberra Hospital, Canberra, ACT, Australia.
authors.forename: G David H
authors.initials: GDH
authors.lastname: Croaker
authors.affiliation: Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
authors.forename: Jimei
authors.initials: J
authors.lastname: Li
authors.affiliation: Eccles Institute of Neuroscience, John Curtin School of Medical Research, the Australian National University, Canberra, ACT, Australia; Medical School, the Australian National University, Canberra, ACT, Australia. Electronic address: zan-min.song@anu.edu.au.
authors.forename: Zan-Min
authors.initials: ZM
authors.lastname: Song
mesh_terms: D000818:Animals; D017209:Apoptosis; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D006624:Hippocampus / Q000503:physiopathology*; D006627:Hirschsprung Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D044023:Receptor, Endothelin B / Q000235:genetics
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D051100:Glial Cell Line-Derived Neurotrophic Factor; D044023:Receptor, Endothelin B
keywords: Endothelin receptor B; Hippocampus, Apoptosis, Cell proliferation, Hirschsprung's disease; Spotting lethal rat