Baylor University, College of Medicine, Howard Hughes Medical Institute; Baylor University, College of Medicine, Department of Molecular and Human Genetics; Baylor University - Jan and Dan Duncan Neurologic Research Institute
Baylor College of Medicine - Howard Hughes Medical Institute; Baylor College of Medicine - Department of Molecular and Human Genetics; Baylor University - Jan and Dan Duncan Neurologic Research Institute
Baylor University, College of Medicine, Department of Molecular and Human Genetics; Baylor University, College of Medicine, MD/PhD Medical Scientist Training Program and MHG Graduate Program
Baylor University, College of Medicine, Department of Molecular and Human Genetics; Baylor University - Jan and Dan Duncan Neurologic Research Institute; Baylor University, College of Medicine, Program in Developmental Biology
Baylor University, College of Medicine, Howard Hughes Medical Institute; Baylor University - Jan and Dan Duncan Neurologic Research Institute; Baylor University, College of Medicine, Program in Developmental Biology; Texas Children’s Hospital - Jan and Dan Duncan Neurologic Research Institute
University of California, Davis - Department of Chemical Engineering; University of California, Davis, College of Biological Sciences, Department of Microbiology and Molecular Genetics
University of California, San Francisco (UCSF) - Department of Cellular and Molecular Pharmacology; University of California, San Francisco (UCSF) - Institute for Quantitative Biosciences (QB3)
Harvard University - Division of Genetics and Genomics; Harvard University - Department of Pediatrics; Harvard University - Manton Center for Orphan Disease Research; Harvard University - Department of Pediatrics; Massachusetts General Hospital, Department of Neurology, Pediatric Neurology Unit
Baylor University, College of Medicine, Department of Pediatrics, Section of Neurology and Developmental Neuroscience; Baylor University - Section of Child Neurology
Baylor University, College of Medicine, Department of Molecular and Human Genetics; Baylor University, College of Medicine, Department of Pediatrics; Baylor University, College of Medicine, Human Genome Sequencing Center
Baylor College of Medicine - Department of Molecular and Human Genetics; Baylor College of Medicine - Howard Hughes Medical Institute; Baylor University - Jan and Dan Duncan Neurologic Research Institute; Baylor University, College of Medicine, MD/PhD Medical Scientist Training Program and MHG Graduate Program; Baylor University, College of Medicine, Program in Developmental Biology
Neuroblasts in flies divide asymmetrically by establishing polarity, distributing cell fate determinants asymmetrically, and positioning their spindle for cell division. The apical complex contains aPKC, Bazooka (Par3), and Par6, and its activity depends on L(2)gl. We show that Ankle2 interacts with L(2)gl and affects aPKC. Reducing Ankle2 levels disrupts 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/VRK1 or l(2)gl suppresses the loss of Ankle2 and restores viability and brain size. The Zika virus NS4A protein interacts with Drosophila Ankle2 and VRK1 in dividing neuroblasts. Human mutational studies implicate this neural cell division pathway in microcephaly and motor neuron disease. In summary, NS4A, ANKLE2, VRK1 and LLGL1 define a novel pathway that impinges on asymmetric determinants of neural stem cell division.
Link, Nichole and Chung, Hyunglok and Jolly, Angad and Withers, Marjorie and Tepe, Burak and Arenkiel, Benjamin R. and Shah, P. S. and Krogan, Nevan J. and Aydin, Hatip and Geckinli, Bilgen B. and Tos, Tulay and Isikay, Sedat and Tuysuz, Beyhan and Mochida, Ganesh H. and Thomas, A. X. and Clark, R. D. and Mirzaa, Ghayda M. and Lupski, James R. and Bellen, Hugo, Ankle2, a Target of Zika Virus, Controls Asymmetric Cell Division of Neuroblasts and Uncovers a Novel Microcephaly Pathway (May 16, 2019). Available at SSRN: https://ssrn.com/abstract=3389483 or http://dx.doi.org/10.2139/ssrn.3389483
This version of the paper has not been formally peer reviewed.
Download This Paper