Severe NDE1-mediated microcephaly results from neural progenitor cell cycle arrests at multiple specific stages
| Autor: | Tiago J. Dantas, David J. Doobin, Richard B. Vallee, Shahrnaz Kemal |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Microcephaly Cell cycle checkpoint Science Models Neurological General Physics and Astronomy Stem cells macromolecular substances Biology Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Neural Stem Cells Cell Movement Pregnancy medicine Animals Humans Cilia RNA Small Interfering Progenitor cell Mitosis Genetics Multidisciplinary FOS: Clinical medicine Neurogenesis Neurosciences Brain Cell Cycle Checkpoints General Chemistry medicine.disease Embryonic stem cell Neural stem cell Rats Cell biology Disease Models Animal Electroporation 030104 developmental biology Gene Knockdown Techniques Mutation Female Stem cell Carrier Proteins Microtubule-Associated Proteins Neuroglia |
| Zdroj: | Nature Communications Nature Communications, Vol 7, Iss 1, Pp 1-14 (2016) |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/ncomms12551 |
| Popis: | Microcephaly is a cortical malformation disorder characterized by an abnormally small brain. Recent studies have revealed severe cases of microcephaly resulting from human mutations in the NDE1 gene, which is involved in the regulation of cytoplasmic dynein. Here using in utero electroporation of NDE1 short hairpin RNA (shRNA) in embryonic rat brains, we observe cell cycle arrest of proliferating neural progenitors at three distinct stages: during apical interkinetic nuclear migration, at the G2-to-M transition and in regulation of primary cilia at the G1-to-S transition. RNAi against the NDE1 paralogue NDEL1 has no such effects. However, NDEL1 overexpression can functionally compensate for NDE1, except at the G2-to-M transition, revealing a unique NDE1 role. In contrast, NDE1 and NDEL1 RNAi have comparable effects on postmitotic neuronal migration. These results reveal that the severity of NDE1-associated microcephaly results not from defects in mitosis, but rather the inability of neural progenitors to ever reach this stage. Human mutations in the NDE1 gene have been associated with cortical malformations and severe microcephaly. Here, the authors show in embryonic rat brains that NDE1-depleted neural progenitors arrest at three specific cell cycle stages before mitosis, resulting in a severe decrease in neurogenesis. |
| Databáze: | OpenAIRE |
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