MAN1 and emerin have overlapping function(s) essential for chromosome segregation and cell division in Caenorhabditis elegans.
Emerin and MAN1 are LEM domain-containing integral membrane proteins of the vertebrate nuclear envelope. The function of MAN1 is unknown, whereas emerin is known to interact with nuclear lamins, barrier-to-autointegration factor (BAF), nesprin-1 alpha, and a transcription repressor. Mutations in emerin cause X-linked recessive Emery-Dreifuss muscular dystrophy. Emerin and MAN1 homologs are both conserved in Caenorhabditis elegans, but loss of Ce-emerin has no detectable phenotype. We therefore used C. elegans to test the hypothesis that Ce-MAN1 overlaps functionally with Ce-emerin. Supporting this model, Ce-MAN1 interacted directly with Ce-lamin and Ce-BAF in vitro and required Ce-lamin for its nuclear envelope localization. Interestingly, RNA interference-mediated removal of approximately 90% of Ce-MAN1 was lethal to approximately 15% of embryos. However, in the absence of Ce-emerin, approximately 90% reduction of Ce-MAN1 was lethal to all embryos by the 100-cell stage, with a phenotype involving repeated cycles of anaphase chromosome bridging and cytokinesis ["cell untimely torn" (cut) phenotype]. Immunostaining showed that the anaphase-bridged chromatin specifically retained a mitosis-specific phosphohistone H3 epitope and failed to recruit detectable Ce-lamin or Ce-BAF. These findings show that LEM domain proteins are essential for cell division and that Ce-emerin and Ce-MAN1 share at least one and possibly multiple overlapping functions, which may be relevant to Emery-Dreifuss muscular dystrophy.
Liu
Jun
J
Department of Molecular Biology and Genetics, 439 Biotechnology Building, Cornell University, Ithaca, NY 14853, USA.
Lee
Kenneth K
KK
Segura-Totten
Miriam
M
Neufeld
Ester
E
Wilson
Katherine L
KL
Gruenbaum
Yosef
Y
D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins; D002455:Cell Division / Q000502:physiology*; D020090:Chromosome Segregation / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D017238:Genes, Helminth; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000235:genetics; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D034622:RNA Interference; D013946:Thymopoietins / Q000235:genetics / Q000378:metabolism*
C501959:BANF1 protein, human; D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; C405329:LEMD3 protein, human; D008565:Membrane Proteins; D009687:Nuclear Proteins; D013946:Thymopoietins; C092710:emerin; C485768:lem-2 protein, C elegans