Mutations in ANKLE2, a ZIKA Virus Target, Disrupt an Asymmetric Cell Division Pathway in Drosophila Neuroblasts to Cause Microcephaly

Dev Cell. 2019 Dec 16;51(6):713-729.e6. doi: 10.1016/j.devcel.2019.10.009. Epub 2019 Nov 14.


The apical Par complex, which contains atypical protein kinase C (aPKC), Bazooka (Par-3), and Par-6, is required for establishing polarity during asymmetric division of neuroblasts in Drosophila, and its activity depends on L(2)gl. We show that loss of Ankle2, a protein associated with microcephaly in humans and known to interact with Zika protein NS4A, reduces brain volume in flies and impacts the function of the Par complex. Reducing Ankle2 levels disrupts endoplasmic reticulum (ER) and nuclear envelope morphology, releasing the kinase Ballchen-VRK1 into the cytosol. These defects are associated with reduced phosphorylation of aPKC, disruption of Par-complex localization, and spindle alignment defects. Importantly, removal of one copy of ballchen or l(2)gl suppresses Ankle2 mutant phenotypes and restores viability and brain size. Human mutational studies implicate the above-mentioned genes in microcephaly and motor neuron disease. We suggest that NS4A, ANKLE2, VRK1, and LLGL1 define a pathway impinging on asymmetric determinants of neural stem cell division.

Keywords: Ballchen; Bazooka; L(2)gl; MCPH16; Miranda; NS4A; VRK1; aPKC; brain development; congenital infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asymmetric Cell Division / physiology*
  • Cell Division
  • Cell Polarity / physiology*
  • Drosophila melanogaster / metabolism
  • Humans
  • Membrane Proteins / genetics*
  • Microcephaly / virology*
  • Mutation
  • Neural Stem Cells / metabolism
  • Neural Stem Cells / virology
  • Neurons / cytology
  • Neurons / metabolism*
  • Nuclear Proteins / genetics*
  • Zika Virus


  • ANKLE2 protein, human
  • Membrane Proteins
  • Nuclear Proteins