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Article: Cerebellar defects in Pdss2 conditional knockout mice during embryonic development and in adulthood
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TitleCerebellar defects in Pdss2 conditional knockout mice during embryonic development and in adulthood
 
AuthorsLu, S1
Lu, LY1 2
Liu, MF1
Yuan, QJ1 1
Sham, MH1
Guan, XY1
Huang, JD1
 
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
 
CitationNeurobiology Of Disease, 2012, v. 45 n. 1, p. 219-233 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.nbd.2011.08.006
 
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.
 
ISSN0969-9961
2012 Impact Factor: 5.624
2012 SCImago Journal Rankings: 2.334
 
DOIhttp://dx.doi.org/10.1016/j.nbd.2011.08.006
 
ISI Accession Number IDWOS:000297883500025
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).

 
ReferencesReferences in Scopus
 
GrantsRole of kinesin-mediated intracellular transportation in Alzheimer's Disease
Protein Trafficking: Mechanism and Diseases
Functions of the ubiquitously expressed kinesin in Purkinje neurons
 
DC FieldValue
dc.contributor.authorLu, S
 
dc.contributor.authorLu, LY
 
dc.contributor.authorLiu, MF
 
dc.contributor.authorYuan, QJ
 
dc.contributor.authorSham, MH
 
dc.contributor.authorGuan, XY
 
dc.contributor.authorHuang, JD
 
dc.date.accessioned2012-05-29T06:05:16Z
 
dc.date.available2012-05-29T06:05:16Z
 
dc.date.issued2012
 
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.
 
dc.description.naturepostprint
 
dc.identifier.citationNeurobiology Of Disease, 2012, v. 45 n. 1, p. 219-233 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.nbd.2011.08.006
 
dc.identifier.citeulike9694203
 
dc.identifier.doihttp://dx.doi.org/10.1016/j.nbd.2011.08.006
 
dc.identifier.epage233
 
dc.identifier.hkuros208628
 
dc.identifier.isiWOS:000297883500025
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).

 
dc.identifier.issn0969-9961
2012 Impact Factor: 5.624
2012 SCImago Journal Rankings: 2.334
 
dc.identifier.issue1
 
dc.identifier.pmid21871565
 
dc.identifier.scopuseid_2-s2.0-81955161104
 
dc.identifier.spage219
 
dc.identifier.urihttp://hdl.handle.net/10722/147654
 
dc.identifier.volume45
 
dc.languageeng
 
dc.publisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/ynbdi
 
dc.publisher.placeUnited States
 
dc.relation.ispartofNeurobiology of Disease
 
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.relation.referencesReferences in Scopus
 
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.subjectApoptosis
 
dc.subjectAtaxia
 
dc.subjectCell migration
 
dc.subjectCerebellum development
 
dc.subjectPDSS2
 
dc.subjectPurkinje cell
 
dc.subjectUbiquinone deficiency
 
dc.titleCerebellar defects in Pdss2 conditional knockout mice during embryonic development and in adulthood
 
dc.typeArticle
 
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<subject>Apoptosis</subject>
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Author Affiliations
  1. The University of Hong Kong
  2. University of Michigan Medical School