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

TitleMutations in ANKLE2, a ZIKA Virus Target, Disrupt an Asymmetric Cell Division Pathway in Drosophila Neuroblasts to Cause Microcephaly.
Publication TypeJournal Article
Year of Publication2019
AuthorsLink, N, Chung, H, Jolly, A, Withers, M, Tepe, B, Arenkiel, BR, Shah, PS, Krogan, NJ, Aydin, H, Geckinli, BB, Tos, T, Isikay, S, Tuysuz, B, Mochida, GH, Thomas, AX, Clark, RD, Mirzaa, GM, Lupski, JR, Bellen, HJ
JournalDev Cell
Volume51
Issue6
Pagination713-729.e6
Date Published2019 12 16
ISSN1878-1551
KeywordsAnimals, Asymmetric Cell Division, Cell Division, Cell Polarity, Drosophila melanogaster, Humans, Membrane Proteins, Microcephaly, Mutation, Neural Stem Cells, Neurons, Nuclear Proteins, Zika Virus
Abstract

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.

DOI10.1016/j.devcel.2019.10.009
Alternate JournalDev Cell
PubMed ID31735666
PubMed Central IDPMC6917859
Grant ListF32 NS092270 / NS / NINDS NIH HHS / United States
R01 DK109934 / DK / NIDDK NIH HHS / United States
R01 NS078294 / NS / NINDS NIH HHS / United States
U54 HD083092 / HD / NICHD NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
K08 NS092898 / NS / NINDS NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States
R01 GM067858 / GM / NIGMS NIH HHS / United States
U54 NS093793 / NS / NINDS NIH HHS / United States
R24 OD022005 / OD / NIH HHS / United States