Ablation of Dido3 compromises lineage commitment of stem cells in vitro and during early embryonic development

By A. Fütterer, Angel Raya, M. Llorente, J. Izpisúa-Belmonte, J. D. L. Pompa, P. Klatt, Carlos Martínez-A. 2011

25 citations recorded by the source corpus.

The death inducer obliterator (Dido) locus encodes three protein isoforms, of which Dido3 is the largest and most broadly expressed. Dido3 is a nuclear protein that forms part of the spindle assembly checkpoint (SAC) and is necessary for correct chromosome segregation in somatic and germ cells. Here we report that specific ablation of Dido3 function in mice causes lethal developmental defects at the onset of gastrulation. Although these defects are associated with centrosome amplification, spindle malformation and a DNA damage response, we provide evidence that embryonic lethality of the Dido3 mutation cannot be explained by its impact on chromosome segregation alone. We show that loss of Dido3 expression compromises differentiation of embryonic stem cells in vitro and of epiblast cells in vivo, resulting in early embryonic death at around day 8.5 of gestation. Close analysis of Dido3 mutant embryoid bodies indicates that ablation of Dido3, rather than producing a generalized differentiation blockade, delays the onset of lineage commitment at the primitive endoderm specification stage. The dual role of Dido3 in chromosome segregation and stem cell differentiation supports the implication of SAC components in stem cell fate decisions.

Subfields: Molecular Biology

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Citations in the corpus

Dido mutations trigger perinatal death and generate brain abnormalities and behavioral alterations in surviving adult mice (2015, methodology): “This dido3 allele is lethal in homozygosis at Theiler embryonic stage ts10–11 and is associated with DNA damage, apoptosis, and growth arrest during embryonic stem (ES) cell differentiation in vitro (18).”
Dido3 PHD modulates cell differentiation and division. (2013, methodology): “…mice were generated by targeting the Dido3-specific exon 16 of the Dido3 locus and were handled in accordance with National and European Union legislation, as well as with approval of the Committee for Ethics in Animal Experimentation of the Centro Nacional de Biotecnología (Fütterer et al., 2012).”
Dido3-dependent SFPQ recruitment maintains efficiency in mammalian alternative splicing (2019, background): “Previous attempts to generate constitutive mutants without Dido3 resulted in an embryonic lethal phenotype (30,52).”
DIDO as a Switchboard that Regulates Self-Renewal and Differentiation in Embryonic Stem Cells (2017, methodology): “Dido3DCT ESCs are unable to differentiate correctly, and can serve as a model to study stem cell self-renewal and differentiation (Futterer et al., 2012).”