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

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Mutations in ANKLE2, a ZIKA Virus Target, Disrupt an Asymmetric Cell Division Pathway in Drosophila Neuroblasts to Cause Microcephaly.
Developmental Cell ( IF 11.8 ) Pub Date : 2019-11-14 , DOI: 10.1016/j.devcel.2019.10.009
Nichole Link ₁ , Hyunglok Chung ₁ , Angad Jolly ₂ , Marjorie Withers ₃ , Burak Tepe ₄ , Benjamin R Arenkiel ₄ , Priya S Shah ₅ , Nevan J Krogan ₆ , Hatip Aydin ₇ , Bilgen B Geckinli ₈ , Tulay Tos ₉ , Sedat Isikay ₁₀ , Beyhan Tuysuz ₁₁ , Ganesh H Mochida ₁₂ , Ajay X Thomas ₁₃ , Robin D Clark ₁₄ , Ghayda M Mirzaa ₁₅ , James R Lupski ₁₆ , Hugo J Bellen ₁₇

Affiliation

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.
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.
Department of Molecular and Human Genetics, 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; Program in Developmental Biology, BCM, Houston, TX 77030, USA.
Department of Chemical Engineering and Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, CA 95616, USA.
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.
Center of Genetics Diagnosis, Zeynep Kamil Maternity and Children's Training and Research Hospital, Istanbul, Turkey.
Department of Medical Genetics, Marmara University School of Medicine, Istanbul, Turkey.
Department of Medical Genetics, Dr. Sami Ulus Research and Training Hospital of Women's and Children's Health and Diseases, Ankara, Turkey.
Department of Physiotherapy and Rehabilitation, Hasan Kalyoncu University, School of Health Sciences, Gaziantep, Turkey.
Department of Pediatrics, Istanbul University-Cerrahpasa, Medical Faculty, Istanbul, Turkey.
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.
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.
Division of Medical Genetics, Department of Pediatrics, Loma Linda University Medical Center, Loma Linda, CA 92354, USA.
Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98105, USA.
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.
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.

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.

中文翻译：

ZIKA 病毒靶点 ANKLE2 的突变破坏了果蝇神经母细胞中的不对称细胞分裂途径，从而导致小头畸形。

含有非典型蛋白激酶 C (aPKC)、火箭筒 (Par-3) 和 Par-6 的顶端 Par 复合物是在果蝇成神经细胞不对称分裂过程中建立极性所必需的，其活性取决于 L(2)gl . 我们表明，Ankle2 是一种与人类小头畸形相关的蛋白质，已知与寨卡病毒 NS4A 相互作用，会减少果蝇的脑容量并影响 Par 复合体的功能。降低 Ankle2 水平会破坏内质网 (ER) 和核膜形态，将激酶 Ballchen-VRK1 释放到细胞质中。这些缺陷与 aPKC 磷酸化减少、Par 复合物定位中断和纺锤体排列缺陷有关。重要的是，去除一份ballchen 或l(2)gl 会抑制Ankle2 突变表型并恢复活力和大脑大小。人类突变研究表明上述基因与小头畸形和运动神经元疾病有关。我们建议 NS4A、ANKLE2、VRK1 和 LLGL1 定义了影响神经干细胞分裂的不对称决定因素的途径。

更新日期：2019-11-14

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