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Article: Cerebellar defects in Pdss2 conditional knockout mice during embryonic development and in adulthood

TitleCerebellar defects in Pdss2 conditional knockout mice during embryonic development and in adulthood
Authors
KeywordsApoptosis
Ataxia
Cell migration
Cerebellum development
PDSS2
Purkinje cell
Ubiquinone deficiency
Issue Date2012
PublisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/ynbdi
Citation
Neurobiology Of Disease, 2012, v. 45 n. 1, p. 219-233 How to Cite?
AbstractPDSS2 is a gene that encodes one of the two subunits of trans-prenyl diphosphate synthase that is essential for ubiquinone biosynthesis. It is known that mutations in PDSS2 can cause primary ubiquinone deficiency in humans and a similar disease in mice. Cerebellum is the most often affected organ in ubiquinone deficiency, and cerebellar atrophy has been diagnosed in many infants with this disease. In this study, two Pdss2 conditional knockout mouse lines directed by Pax2-cre and Pcp2-cre were generated to investigate the effect of ubiquinone deficiency on cerebellum during embryonic development and in adulthood, respectively. The Pdss2 f/-; Pax2-cre mouse recapitulates some symptoms of ubiquinone deficiency in infants, including severe cerebellum hypoplasia and lipid accumulation in skeletal muscles at birth. During early cerebellum development (E12.5-14.5), Pdss2 knockout initially causes the delay of radial glial cell growth and neuron progenitor migration, so the growth of mutant cerebellum is retarded. During later development (E15.5-P0), increased ectopic apoptosis of neuroblasts and impaired cell proliferation result in the progression of cerebellum hypoplasia in the mutant. Thus, the mutant cerebellum contains fewer neurons at birth, and the cells are disorganized. The developmental defect of mutant cerebellum does not result from reduced Fgf8 expression before E12.5. Electron microscopy reveals mitochondrial defects and increased autophagic-like vacuolization that may arise in response to abnormal mitochondria in the mutant cerebellum. Nevertheless, the mutant mice die soon after birth probably due to cleft palate and micrognathia, which may result from Pdss2 knockout caused by ectopic Pax2-cre expression in the first branchial arch. On the other hand, the Pdss2 f/-; Pcp2-cre mouse is healthy at birth but gradually loses cerebellar Purkinje cells and develops ataxia-like symptoms at 9.5months; thus this conditional knockout mouse may serve as a model for ubiquinone deficiency in adult patients. In conclusion, this study provides two mouse models of Pdss2 based ubiquinone deficiency. During cerebellum development, Pdss2 knockout results in severe cerebellum hypoplasia by impairing cell migration and eliciting ectopic apoptosis, whereas Pdss2 knockout in Purkinje cells at postnatal stages leads to the development of cerebellar ataxia. © 2011 Elsevier Inc.
Persistent Identifierhttp://hdl.handle.net/10722/147654
ISSN
2014 Impact Factor: 5.078
2014 SCImago Journal Rankings: 2.441
ISI Accession Number ID
Funding AgencyGrant Number
Hong Kong Research Grants CouncilHKU 7321/04M
HKU 7636/05M
RGC GroupHKUST6/CRF/08
Funding Information:

We thank Ms. Sheila Tsang for her great help in the blastocyst injection. We also thank Dr. A Groves for providing Pax2-Cre mice and Prof. K. SE. Cheah in the Department of Biochemistry. University of Hong Kong, for giving us Pax2-cre deleter mouse line and Fgf8 probe plasmid. This work was supported by grants from the Hong Kong Research Grants Council (HKU 7321/04M; HKU 7636/05M) to J.D.H., and partially by a RGC Group Research Project (HKUST6/CRF/08).

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DC FieldValueLanguage
dc.contributor.authorLu, Sen_HK
dc.contributor.authorLu, LYen_HK
dc.contributor.authorLiu, MFen_HK
dc.contributor.authorYuan, QJen_HK
dc.contributor.authorSham, MHen_HK
dc.contributor.authorGuan, XYen_HK
dc.contributor.authorHuang, JDen_HK
dc.date.accessioned2012-05-29T06:05:16Z-
dc.date.available2012-05-29T06:05:16Z-
dc.date.issued2012en_HK
dc.identifier.citationNeurobiology Of Disease, 2012, v. 45 n. 1, p. 219-233en_HK
dc.identifier.issn0969-9961en_HK
dc.identifier.urihttp://hdl.handle.net/10722/147654-
dc.description.abstractPDSS2 is a gene that encodes one of the two subunits of trans-prenyl diphosphate synthase that is essential for ubiquinone biosynthesis. It is known that mutations in PDSS2 can cause primary ubiquinone deficiency in humans and a similar disease in mice. Cerebellum is the most often affected organ in ubiquinone deficiency, and cerebellar atrophy has been diagnosed in many infants with this disease. In this study, two Pdss2 conditional knockout mouse lines directed by Pax2-cre and Pcp2-cre were generated to investigate the effect of ubiquinone deficiency on cerebellum during embryonic development and in adulthood, respectively. The Pdss2 f/-; Pax2-cre mouse recapitulates some symptoms of ubiquinone deficiency in infants, including severe cerebellum hypoplasia and lipid accumulation in skeletal muscles at birth. During early cerebellum development (E12.5-14.5), Pdss2 knockout initially causes the delay of radial glial cell growth and neuron progenitor migration, so the growth of mutant cerebellum is retarded. During later development (E15.5-P0), increased ectopic apoptosis of neuroblasts and impaired cell proliferation result in the progression of cerebellum hypoplasia in the mutant. Thus, the mutant cerebellum contains fewer neurons at birth, and the cells are disorganized. The developmental defect of mutant cerebellum does not result from reduced Fgf8 expression before E12.5. Electron microscopy reveals mitochondrial defects and increased autophagic-like vacuolization that may arise in response to abnormal mitochondria in the mutant cerebellum. Nevertheless, the mutant mice die soon after birth probably due to cleft palate and micrognathia, which may result from Pdss2 knockout caused by ectopic Pax2-cre expression in the first branchial arch. On the other hand, the Pdss2 f/-; Pcp2-cre mouse is healthy at birth but gradually loses cerebellar Purkinje cells and develops ataxia-like symptoms at 9.5months; thus this conditional knockout mouse may serve as a model for ubiquinone deficiency in adult patients. In conclusion, this study provides two mouse models of Pdss2 based ubiquinone deficiency. During cerebellum development, Pdss2 knockout results in severe cerebellum hypoplasia by impairing cell migration and eliciting ectopic apoptosis, whereas Pdss2 knockout in Purkinje cells at postnatal stages leads to the development of cerebellar ataxia. © 2011 Elsevier Inc.en_HK
dc.languageengen_US
dc.publisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/ynbdien_HK
dc.relation.ispartofNeurobiology of Diseaseen_HK
dc.rightsNOTICE: this is the author’s version of a work that was accepted for publication in Neurobiology Of Disease. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Neurobiology Of Disease, 2012, v. 45 n. 1, p. 219-233. DOI: 10.1016/j.nbd.2011.08.006-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subjectApoptosisen_HK
dc.subjectAtaxiaen_HK
dc.subjectCell migrationen_HK
dc.subjectCerebellum developmenten_HK
dc.subjectPDSS2en_HK
dc.subjectPurkinje cellen_HK
dc.subjectUbiquinone deficiencyen_HK
dc.titleCerebellar defects in Pdss2 conditional knockout mice during embryonic development and in adulthooden_HK
dc.typeArticleen_HK
dc.identifier.emailGuan, XY:xyguan@hkucc.hku.hken_HK
dc.identifier.emailHuang, JD:jdhuang@hkucc.hku.hken_HK
dc.identifier.authorityGuan, XY=rp00454en_HK
dc.identifier.authorityHuang, JD=rp00451en_HK
dc.description.naturepostprinten_US
dc.identifier.doi10.1016/j.nbd.2011.08.006en_HK
dc.identifier.pmid21871565-
dc.identifier.scopuseid_2-s2.0-81955161104en_HK
dc.identifier.hkuros208628-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-81955161104&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume45en_HK
dc.identifier.issue1en_HK
dc.identifier.spage219en_HK
dc.identifier.epage233en_HK
dc.identifier.isiWOS:000297883500025-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectRole of kinesin-mediated intracellular transportation in Alzheimer's Disease-
dc.relation.projectProtein Trafficking: Mechanism and Diseases-
dc.relation.projectFunctions of the ubiquitously expressed kinesin in Purkinje neurons-
dc.identifier.scopusauthoridLu, S=37072888300en_HK
dc.identifier.scopusauthoridLu, LY=54780283500en_HK
dc.identifier.scopusauthoridLiu, MF=54780140600en_HK
dc.identifier.scopusauthoridYuan, QJ=7202814773en_HK
dc.identifier.scopusauthoridSham, MH=54780623500en_HK
dc.identifier.scopusauthoridGuan, XY=7201463221en_HK
dc.identifier.scopusauthoridHuang, JD=8108660600en_HK
dc.identifier.citeulike9694203-

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