@article{587c85f2196240f8a41b304374e25082,
title = "Mutations in ANKLE2, a ZIKA Virus Target, Disrupt an Asymmetric Cell Division Pathway in Drosophila Neuroblasts to Cause Microcephaly",
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.",
keywords = "aPKC, Ballchen, Bazooka, brain development, congenital infection, L(2)gl, MCPH16, Miranda, NS4A, VRK1",
author = "Nichole Link and Hyunglok Chung and Angad Jolly and Marjorie Withers and Burak Tepe and Arenkiel, {Benjamin R.} and Shah, {Priya S.} and Krogan, {Nevan J.} and Hatip Aydin and Geckinli, {Bilgen B.} and Tulay Tos and Sedat Isikay and Beyhan Tuysuz and Mochida, {Ganesh H.} and Thomas, {Ajay X.} and Clark, {Robin D.} and Mirzaa, {Ghayda M.} and Lupski, {James R.} and Bellen, {Hugo J.}",
note = "Funding Information: We would like to thank many members of the Bellen lab for suggestions and Megan Campbell and Karen Schulze for critical reading. We thank Chris Doe, Jurgen Knoblich, Jim Skeath, Kenneth Prehoda, Alf Herzig, Hiroyuki Ohkura, and the Bloomington Drosophila Stock Center for providing stocks and reagents and the IDDRC Microscopy Core (NIH/NICHD U54 HD083092) for valuable input. This work was supported by NIH/NINDS F32NS092270 to N.L.; Howard Hughes Medical Institute (HHMI) Medical Research Fellowship to A.J.; the NIH/NINDS K08NS092898 and Jordan's Guardian Angels to G.M.M.; a jointly funded NHGRI and NHLBI grant to the Baylor-Hopkins Center for Mendelian Genomics (UM1 HG006542); NIH/NINDS R35NS105078 to J.R.L; and NIH U54NS093793, NIH R24OD022005, and the Huffington Foundation to H.J.B. N.L. and H.C. are supported by HHMI and H.J.B. is an Investigator of the Howard Hughes Medical Institute. N.L. and H.J.B. conceived the project, designed the experiments, and wrote and revised the manuscript with J.R.L. H.C. performed the in vivo Ankle2 immunoprecipitations and assessed protein levels. A.J. assisted with the brain volume measurements. A.J. M.W. and J.R.L. performed the primary fibroblast experiments and human mutation studies. H.A. B.B.G. T.T. S.I. B.T. G.M.M. G.H.M. A.X.T. and R.D.C. ascertained the clinical and molecular data of children with variants. B.T. B.R.A. P.S.S. and N.J.K. assisted with the Zika virus experiments. N.L. performed all other experiments. The authors declare no competing interests. Funding Information: We would like to thank many members of the Bellen lab for suggestions and Megan Campbell and Karen Schulze for critical reading. We thank Chris Doe, Jurgen Knoblich, Jim Skeath, Kenneth Prehoda, Alf Herzig, Hiroyuki Ohkura, and the Bloomington Drosophila Stock Center for providing stocks and reagents and the IDDRC Microscopy Core (NIH/ NICHD U54 HD083092 ) for valuable input. This work was supported by NIH/ NINDS F32NS092270 to N.L.; Howard Hughes Medical Institute (HHMI) Medical Research Fellowship to A.J.; the NIH/NINDS K08NS092898 and Jordan{\textquoteright}s Guardian Angels to G.M.M.; a jointly funded NHGRI and NHLBI grant to the Baylor-Hopkins Center for Mendelian Genomics ( UM1 HG006542 ); NIH/NINDS R35NS105078 to J.R.L; and NIH U54NS093793 , NIH R24OD022005 , and the Huffington Foundation to H.J.B. N.L. and H.C. are supported by HHMI and H.J.B. is an Investigator of the Howard Hughes Medical Institute. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = dec,
day = "16",
doi = "10.1016/j.devcel.2019.10.009",
language = "English (US)",
volume = "51",
pages = "713--729.e6",
journal = "Developmental Cell",
issn = "1534-5807",
publisher = "Cell Press",
number = "6",
}