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Disruption of the Mouse Tip110 Gene Leads to Early Post‐implantation Lethality and Prohibits Embryonic Stem Cell Development
Author(s) -
Whitmill Amanda Jade,
He Johnny
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.748.6
Subject(s) - biology , embryonic stem cell , sox2 , microbiology and biotechnology , blastocyst , homeobox protein nanog , stem cell , embryo , embryogenesis , genetics , induced pluripotent stem cell , gene
HIV‐1 Tat‐interacting protein of 110 kDa, Tip110, has roles in tumor antigen presentation, pre‐mRNA splicing, transcription of viral and host genes (e.g. HIV‐1 LTR and androgen receptor), and protein degradation. Tip110 is also known to be up‐regulated in a variety of cancers and to regulate and/or interact with a variety of transcription factors, oncogenes, and pluripotency factors such as YB1, USP4, USP15, CMYC, GATA2, OCT4, SOX2 and NANOG. As such, Tip110 can effect proliferation, apoptosis, and the cell cycle when knocked down in vitro . However, Tip110 function in embryonic development remains largely uncharacterized. One early study has shown that loss of a Tip110 ortholog leads to embryonic lethality in zebrafish. Our studies have shown that transgenic mice lacking expression of a functional Tip110 protein die several days post‐implantation in vivo . Tip110 loss does not impair embryo growth from the zygote to the blastocyst stage in vivo nor does it impair the blastocysts ability to implant into the uterine lining in vivo . However, long‐term culture of blastocysts in vitro reveals that Tip110 loss impairs both blastocyst outgrowth formation and derivation of mouse embryonic stem cells (mESC) from blastocysts in vitro . In this case, blastocyst outgrowths lacking Tip110 develop initially in synchrony with their Tip110 expressing counterparts but diminish in both size and survivability with long‐term culture. In vivo embryos can survive until the post‐implantation stage where they will eventually perish. The premature death of these embryos is characterized by a clear retardation in embryonic development resulting in underdeveloped or completely resorbed mouse embryos around 8.5 days post coitum (dpc). The underdeveloped embryos possess clear features of premature developmental arrest between 8.5 and 9.5 dpc including failure of anterior and posterior neuropore closure, lack of characteristic s‐shaped looping of the heart, minimal somatogenesis, and diminished formation of yolk‐sac blood islands. Microarray analysis of Tip110 −/− cells derived from mouse blastocysts is currently underway to determine the specific underlying mechanisms that lead to cell death in Tip110 −/− mESCs and embryos.