title: Nuclear envelope structural proteins facilitate nuclear shape changes accompanying embryonic differentiation and fidelity of gene expression.
abstract: BACKGROUND
  Nuclear size and shape are specific to a cell type, function, and location, and can serve as indicators of disease and development. We previously found that lamin A/C and associated nuclear envelope structural proteins were upregulated when murine embryonic stem (ES) cells differentiated to primitive endoderm cells. Here we further investigated the morphological changes of nuclei that accompany this differentiation.
  
  
  RESULTS
  The nuclei of undifferentiated wild type cells were found shaped as flattened, irregular ovals, whereas nuclei of Gata4-positive endoderm cells were more spherical, less flattened, and with a slightly reduced volume. The morphological change was confirmed in the trophectoderm and primitive endoderm lineages of E4.5 blastocysts, compared to larger and more irregularly shaped of the nuclei of the inner cell mass. We established ES cells genetically null for the nuclear lamina proteins lamin A/C or the inner nuclear envelope protein emerin, or compound mutant for both lamin A/C and emerin. ES cells deficient in lamin A/C differentiated to endoderm but less efficiently, and the nuclei remained flattened and failed to condense. The size and shape of emerin-deficient nuclei also remained uncondensed after treatment with RA. The emerin/lamin A/C double knockout ES cells failed to differentiate to endoderm cells, though the nuclei condensed but retained a generally flattened ellipsoid shape. Additionally, ES cells deficient for lamin A/C and/or emerin had compromised ability to undergo endoderm differentiation, where the differentiating cells often exhibited coexpression of pluripotent and differentiation markers, such as Oct3/4 and Gata4, respectively, indicating an infidelity of gene regulation.
  
  
  CONCLUSIONS
  The results suggest that changes in nuclear size and shape, which are mediated by nuclear envelope structural proteins lamin A/C and/or emerin, also impact gene regulation and lineage differentiation in early embryos. Nevertheless, mice lacking both lamin A/C and emerin were born at the expected frequency, indicating their embryonic development is completed despite the observed protein deficiency.
authors.affiliation: Department of Cell Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Papanicolaou Building, Room 415 [M877] 1550 NW 10th Avenue, Miami, FL, 33136, USA. esmith@med.miami.edu.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Smith
authors.affiliation: Department of Cell Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Papanicolaou Building, Room 415 [M877] 1550 NW 10th Avenue, Miami, FL, 33136, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Meng
authors.affiliation: Department of Cell Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Papanicolaou Building, Room 415 [M877] 1550 NW 10th Avenue, Miami, FL, 33136, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Moore
authors.affiliation: Department of Cell Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Papanicolaou Building, Room 415 [M877] 1550 NW 10th Avenue, Miami, FL, 33136, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Tse
authors.affiliation: Department of Cell Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Papanicolaou Building, Room 415 [M877] 1550 NW 10th Avenue, Miami, FL, 33136, USA.
authors.forename: Arn G
authors.initials: AG
authors.lastname: Xu
authors.affiliation: Department of Cell Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Papanicolaou Building, Room 415 [M877] 1550 NW 10th Avenue, Miami, FL, 33136, USA.
authors.forename: Xiang-Xi
authors.initials: XX
authors.lastname: Xu
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000166:cytology; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics; D053144:Cell Nucleus Shape / Q000235:genetics*; D002478:Cells, Cultured; D003433:Crosses, Genetic; D058732:Embryoid Bodies / Q000166:cytology / Q000648:ultrastructure; D047108:Embryonic Development / Q000235:genetics; D004707:Endoderm / Q000166:cytology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D034904:Lamin Type A / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D009685:Nuclear Envelope / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*
chemical_list: D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; C092710:emerin
keywords: Emerin; Endoderm; Lamin A/C; Mouse ES cells; Nuclear envelope; Retinoic acid