Abstract

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.

Highlights

  • (C) Rescue of NDE1 and NDEL1 mRNA levels by RNAi‐insensitive cDNA of either NDE1 or NDEL1

  • E16 rat embryonic brains were electroporated with shRNAs to the various conditions described below

  • 10μm. 2‐channel composite is presented with electroporation signal in green and immunocytochemical signal in magenta. 3‐channel composite is presented with electroporation signal in green, immunocytochemical signal in red, and DAPI in blue

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Summary

Introduction

E16 rat embryonic brains were electroporated with shRNAs to the various conditions described below. 2‐channel composite is presented with electroporation signal in green and immunocytochemical signal in magenta.

Results
Conclusion
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