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Blastomere Explants to Test for Cell Fate Commitment During Embryonic Development
Published on: January 26, 2013
Ablation of Dido3 compromises lineage commitment of stem cells in vitro and during early embryonic development
A Fütterer1, A Raya, M Llorente
1Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB/CSIC), Cantoblanco, Madrid, Spain.
Abstract:
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.
Insights
Loss of Dido3 protein function in mice causes lethal developmental defects during gastrulation. This is due to impaired stem cell differentiation and delayed lineage commitment, not solely chromosome segregation issues.
Area of Science:
- Developmental Biology
- Cell Biology
- Genetics
Background:
- The death inducer obliterator (Dido) locus encodes multiple protein isoforms, with Dido3 being the largest and most widely expressed.
- Dido3 is a nuclear protein crucial for the spindle assembly checkpoint (SAC) and accurate chromosome segregation in both somatic and germ cells.
Purpose of the Study:
- To investigate the function of Dido3 in mouse development.
- To determine the cause of embryonic lethality observed in Dido3-deficient mice.
- To explore the role of Dido3 in stem cell differentiation and lineage commitment.
Main Methods:
- Generation and analysis of Dido3-ablated mice.
- In vitro differentiation of embryonic stem cells.
- In vivo analysis of epiblast cell differentiation.
- Microscopic examination of centrosome and spindle formation.
- Assessment of DNA damage response.
Main Results:
- Specific ablation of Dido3 function in mice leads to lethal developmental defects at gastrulation.
- Mutant embryos exhibit centrosome amplification, spindle malformation, and DNA damage.
- Loss of Dido3 compromises embryonic stem cell differentiation in vitro and epiblast cell differentiation in vivo.
- Dido3 deficiency delays, rather than blocks, primitive endoderm specification and lineage commitment.
Conclusions:
- Embryonic lethality in Dido3-mutant mice is linked to compromised stem cell differentiation and delayed lineage commitment, beyond its role in chromosome segregation.
- The findings suggest a dual role for Dido3 in both chromosome segregation and stem cell fate decisions.
- Spindle assembly checkpoint components may play a significant role in regulating stem cell fate decisions.
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