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Loss of CDK5RAP2 affects neural but not non-neural mESC differentiation into cardiomyocytes
Nadine Kraemer1, Ethiraj Ravindran, Sami Zaqout
1a Institute of Cell Biology and Neurobiology; Charité - Universitätsmedizin Berlin; Campus Mitte ; Berlin , Germany.
Abstract:
Biallelic mutations in the gene encoding centrosomal CDK5RAP2 lead to autosomal recessive primary microcephaly (MCPH), a disorder characterized by pronounced reduction in volume of otherwise architectonical normal brains and intellectual deficit. The current model for the microcephaly phenotype in MCPH invokes a premature shift from symmetric to asymmetric neural progenitor-cell divisions with a subsequent depletion of the progenitor pool. The isolated neural phenotype, despite the ubiquitous expression of CDK5RAP2, and reports of progressive microcephaly in individual MCPH cases prompted us to investigate neural and non-neural differentiation of Cdk5rap2-depleted and control murine embryonic stem cells (mESC). We demonstrate an accumulating proliferation defect of neurally differentiating Cdk5rap2-depleted mESC and cell death of proliferative and early postmitotic cells. A similar effect does not occur in non-neural differentiation into beating cardiomyocytes, which is in line with the lack of non-central nervous system features in MCPH patients. Our data suggest that MCPH is not only caused by premature differentiation of progenitors, but also by reduced propagation and survival of neural progenitors.
Insights
Mutations in the CDK5RAP2 gene cause primary microcephaly (MCPH), leading to intellectual deficits. This study reveals that Cdk5rap2 depletion impairs neural progenitor proliferation and survival, not just differentiation.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Autosomal recessive primary microcephaly (MCPH) is linked to CDK5RAP2 gene mutations.
- MCPH involves brain volume reduction and intellectual disability.
- Existing models suggest premature neural progenitor cell division shifts cause MCPH.
Purpose of the Study:
- Investigate the role of CDK5RAP2 in neural and non-neural differentiation.
- Clarify the cellular mechanisms underlying the microcephaly phenotype.
- Determine if Cdk5rap2 depletion affects neural progenitor cell proliferation and survival.
Main Methods:
- Utilized murine embryonic stem cells (mESC) for differentiation studies.
- Depleted Cdk5rap2 expression in mESC.
- Compared neural differentiation pathways between depleted and control mESC.
- Assessed cardiomyocyte differentiation as a non-neural control.
Main Results:
- Cdk5rap2-depleted mESC exhibited accumulating proliferation defects during neural differentiation.
- Significant cell death observed in proliferative and early postmitotic neural progenitors.
- Non-neural differentiation into cardiomyocytes was unaffected.
- Neural-specific defects align with the isolated neurological presentation of MCPH.
Conclusions:
- MCPH pathogenesis involves more than just premature progenitor differentiation.
- Reduced propagation and survival of neural progenitors are critical factors.
- CDK5RAP2 is essential for maintaining neural progenitor pool integrity.
- Findings support a dual mechanism of progenitor depletion in MCPH.
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