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Dev Cell. 2019 Nov 14. pii: S1534-5807(19)30853-6. doi: 10.1016/j.devcel.2019.10.009. [Epub ahead of print]

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

Author information

1
Howard Hughes Medical Institute, BCM, Houston, TX 77030, USA; Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
2
Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; MD/PhD Medical Scientist Training Program and MHG Graduate program, BCM, Houston, TX 77030, USA.
3
Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA.
4
Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Program in Developmental Biology, BCM, Houston, TX 77030, USA.
5
Department of Chemical Engineering and Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, CA 95616, USA.
6
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; California Institute for Quantitative Biosciences, QB3, University of California, San Francisco, San Francisco, CA 94158, USA.
7
Center of Genetics Diagnosis, Zeynep Kamil Maternity and Children's Training and Research Hospital, Istanbul, Turkey.
8
Department of Medical Genetics, Marmara University School of Medicine, Istanbul, Turkey.
9
Department of Medical Genetics, Dr. Sami Ulus Research and Training Hospital of Women's and Children's Health and Diseases, Ankara, Turkey.
10
Department of Physiotherapy and Rehabilitation, Hasan Kalyoncu University, School of Health Sciences, Gaziantep, Turkey.
11
Department of Pediatrics, Istanbul University-Cerrahpasa, Medical Faculty, Istanbul, Turkey.
12
Division of Genetics and Genomics, Department of Pediatrics and Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Pediatric Neurology Unit, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
13
Department of Pediatrics, Section of Neurology and Developmental Neuroscience, BCM, Houston, TX 77030, USA; Section of Child Neurology, Texas Children's Hospital, Houston, TX 77030, USA.
14
Division of Medical Genetics, Department of Pediatrics, Loma Linda University Medical Center, Loma Linda, CA 92354, USA.
15
Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98105, USA.
16
Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Department of Pediatrics, BCM, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
17
Howard Hughes Medical Institute, BCM, Houston, TX 77030, USA; Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; MD/PhD Medical Scientist Training Program and MHG Graduate program, BCM, Houston, TX 77030, USA; Program in Developmental Biology, BCM, Houston, TX 77030, USA. Electronic address: hbellen@bcm.edu.

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:

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

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