ArticleHuman molecular genetics2019
p53 deletion rescues lethal microcephaly in a mouse model with neural stem cell abscission defects.
Article in Human molecular genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 42 citations in OpenAlex.
- Rare genetic causes of primary microcephaly in two Saudi families identified via whole-exome sequencing: Genomic and phenotypic delineation of pathogenicMolecular genetics and metabolism reports · 2026Article
- Cytokinetic abscission failures in a polarized epithelium affect apical membrane size and cilia.Molecular biology of the cell · 2026Article
- The midbody and midbody remnant: from cellular debris to signaling organelle with diagnostic and therapeutic potential.Molecular biology of the cell · 2025Review
- mRNA stability fine-tunes gene expression in the developing cortex to control neurogenesis.PLoS biology · 2025Article
- Altered tubulin detyrosination due to SVBP malfunction induces cytokinesis failure and senescence, underlying a complex hereditary spastic paraplegia.Aging cell · 2025Article
- Aberrant generation of dentate gyrus granule cells is associated with epileptic susceptibility in p53 conditional knockout mice.Frontiers in neuroscience · 2024Article
- An entosis-like process induces mitotic disruption in Pals1 microcephaly pathogenesis.Nature communications · 2023Article
- P53 independent pathogenic mechanisms contribute to BubR1 microcephaly.Frontiers in cell and developmental biology · 2023Article
- Tissue-wide genetic and cellular landscape shapes the execution of sequential PRC2 functions in neural stem cell lineage progression.Science advances · 2022Article
- Loss of non-motor kinesin KIF26A causes congenital brain malformations via dysregulated neuronal migration and axonal growth as well as apoptosis.Developmental cell · 2022Article
- Emerging roles of centrosome cohesion.Open biology · 2022Review
- Resetting Proteostasis of CIRBP with ISRIB Suppresses Neural Stem Cell Apoptosis under Hypoxic Exposure.Oxidative medicine and cellular longevity · 2022Article
- Modeling Human Primary Microcephaly With hiPSC-Derived Brain Organoids Carrying CPAP-E1235V Disease-Associated Mutant Protein.Frontiers in cell and developmental biology · 2022Article
- Non-Structural Protein 5 of Zika Virus Interacts with p53 in Human Neural Progenitor Cells and Induces p53-Mediated Apoptosis.Virologica Sinica · 2021Article
- Cytokinetic Abscission Regulation in Neural Stem Cells and Tissue Development.Current stem cell reports · 2021Article
- Trp53 ablation fails to prevent microcephaly in mouse pallium with impaired minor intron splicing.Development (Cambridge, England) · 2021Article
- Deficient adaptation to centrosome duplication defects in neural progenitors causes microcephaly and subcortical heterotopias.JCI insight · 2021Article
- Puma- and Caspase9-mediated apoptosis is dispensable for p53-driven neural crest-based developmental defects.Cell death and differentiation · 2021Article
- Human Microcephaly ProteinCells · 2021Article
- Loss of Coiled-Coil Protein Cep55 Impairs Neural Stem Cell Abscission and Results in p53-Dependent Apoptosis in Developing Cortex.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2021Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Building a cerebral cortex of the proper size involves balancing rates and timing of neural stem cell (NSC) proliferation, neurogenesis and cell death. The cellular mechanisms connecting genetic mutations to brain malformation phenotypes are still poorly understood. Microcephaly may result when NSC divisions are too slow, produce neurons too early or undergo apoptosis but the relative contributions of these cellular mechanisms to various types of microcephaly are not understood. We previously showed that mouse mutants in Kif20b (formerly called Mphosph1, Mpp1 or KRMP1) have small cortices that show elevated apoptosis and defects in maturation of NSC midbodies, which mediate cytokinetic abscission. Here we test the contribution of intrinsic NSC apoptosis to brain size reduction in this lethal microcephaly model. By making double mutants with the pro-apoptotic genes Bax and Trp53 (p53), we find that p53-dependent apoptosis of cortical NSCs accounts for most of the microcephaly, but that there is a significant apoptosis-independent contribution as well. Remarkably, heterozygous p53 deletion is sufficient to fully rescue survival of the Kif20b mutant into adulthood. In addition, the NSC midbody maturation defects are not rescued by p53 deletion, showing that they are either upstream of p53 activation, or in a parallel pathway. Accumulation of p53 in the nucleus of mutant NSCs at midbody stage suggests the possibility of a novel midbody-mediated pathway for p53 activation. This work elucidates both NSC apoptosis and abscission mechanisms that could underlie human microcephaly or other brain malformations.
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