title: Growth arrest in the ribosomopathy, Bowen-Conradi syndrome, is due to dramatically reduced cell proliferation and a defect in mitotic progression.
abstract: Bowen-Conradi syndrome (BCS) is a ribosomopathy characterized by severe developmental delay and growth failure that typically leads to death by one year of age. It is caused by a c.257A>G, p.D86G substitution in the ribosomal biogenesis protein, Essential for Mitotic Growth 1 (EMG1). We generated a knock-in of the D86G substitution in mice to characterize the effects of EMG1 deficiency, particularly in the brain, where EMG1 expression is high. Embryos homozygous for the mutation in Emg1 were small for gestational age with neural tube defects, and died between embryonic days 8.5 and 12.5. These embryos exhibited dramatically reduced cell proliferation, which we also detected in autopsy brain tissue and bone marrow of BCS patients, consistent with a requirement for high levels of EMG1 in tissues with rapid cell proliferation. In fibroblasts derived from the BCS mouse embryos, we detected a high proportion of binucleated cells, indicating that a mitotic defect underlies the growth arrest in BCS. These studies add to growing evidence of a link between ribosome biogenesis, mitotic progression, and brain development that is currently unexplored.
authors.affiliation: Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada; Manitoba Institute of Child Health, Winnipeg, MB, Canada; Institute of Developmental Biology, University of Cologne, Cologne, Germany. Electronic address: joyarmistead@gmail.com.
authors.forename: Joy
authors.initials: J
authors.lastname: Armistead
authors.affiliation: Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada. Electronic address: nehalpatel2001@yahoo.com.
authors.forename: Nehal
authors.initials: N
authors.lastname: Patel
authors.affiliation: Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada. Electronic address: Xiaoli.Wu@med.umanitoba.ca.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada. Electronic address: hemming@cc.umanitoba.ca.
authors.forename: Richard
authors.initials: R
authors.lastname: Hemming
authors.affiliation: Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada; Manitoba Institute of Child Health, Winnipeg, MB, Canada. Electronic address: biswajit.chowdhury@gmail.com.
authors.forename: Biswajit
authors.initials: B
authors.lastname: Chowdhury
authors.affiliation: Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada. Electronic address: drgaganbasra@gmail.com.
authors.forename: Gagandeep Singh
authors.initials: GS
authors.lastname: Basra
authors.affiliation: Department of Pathology, University of Manitoba, Winnipeg, MB, Canada; Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada; Manitoba Institute of Child Health, Winnipeg, MB, Canada. Electronic address: marc.delbigio@med.umanitoba.ca.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Del Bigio
authors.affiliation: Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada. Electronic address: hao.ding@med.umanitoba.ca.
authors.forename: Hao
authors.initials: H
authors.lastname: Ding
authors.affiliation: Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada; Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada; Manitoba Institute of Child Health, Winnipeg, MB, Canada. Electronic address: Barbara.Triggs-Raine@med.umanitoba.ca.
authors.forename: Barbara
authors.initials: B
authors.lastname: Triggs-Raine
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001921:Brain / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D002466:Cell Nucleolus / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics*; D002478:Cells, Cultured; D002648:Child; D004622:Embryo, Mammalian / Q000166:cytology; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D015151:Immunoblotting; D007231:Infant, Newborn; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D008938:Mitosis / Q000235:genetics*; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011596:Psychomotor Disorders / Q000235:genetics* / Q000473:pathology; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism
chemical_list: C556162:EMG1 protein, mouse; D009687:Nuclear Proteins
keywords: Bowen–Conradi syndrome; Intrauterine growth retardation; Mitotic progression; Proliferation; Ribosome biogenesis; Ribosomopathy