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Ankle2, a Target of Zika Virus, Controls Asymmetric Cell Division of Neuroblasts and Uncovers a Novel Microcephaly Pathway

72 Pages Posted: 18 May 2019 Sneak Peek Status: Under Review

See all articles by Nichole Link

Nichole Link

Baylor University, College of Medicine, Howard Hughes Medical Institute; Baylor University, College of Medicine, Department of Molecular and Human Genetics; Texas Children's Hospital - Jan and Dan Duncan Neurologic Research Institute

Hyunglok Chung

Baylor College of Medicine - Howard Hughes Medical Institute; Baylor College of Medicine - Department of Molecular and Human Genetics; Texas Children's Hospital - Jan and Dan Duncan Neurologic Research Institute

Angad Jolly

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

Marjorie Withers

Baylor University, College of Medicine, Department of Molecular and Human Genetics

Burak Tepe

Baylor University, College of Medicine, Department of Molecular and Human Genetics; Texas Children's Hospital - Jan and Dan Duncan Neurologic Research Institute; Baylor University, College of Medicine, Program in Developmental Biology

Benjamin R. Arenkiel

Baylor University, College of Medicine, Howard Hughes Medical Institute; Texas Children's Hospital - 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

P. S. Shah

University of California, Davis - Department of Chemical Engineering; University of California, Davis, College of Biological Sciences, Department of Microbiology and Molecular Genetics

Nevan J. Krogan

University of California, San Francisco (UCSF) - Department of Cellular and Molecular Pharmacology; University of California, San Francisco (UCSF) - Institute for Quantitative Biosciences (QB3)

Hatip Aydin

Zeynep Kamil Maternity and Children's Training and Research Hospital - Center of Genetics Diagnosis

Bilgen B. Geckinli

Marmara University, School of Medicine, Department of Medical Genetics

Tulay Tos

Dr. Sami Ulus Research and Training Hospital of Women's and Children's Health and Diseases - Department of Medical Genetics

Sedat Isikay

Hasan Kalyoncu University, School of Health Sciences, Department of Physiotherapy and Rehabilitation

Beyhan Tuysuz

Istanbul University, Cerrahpasa Faculty of Medicine, Department of Pediatrics

Ganesh H. Mochida

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

A. X. Thomas

Baylor University, College of Medicine, Department of Pediatrics, Section of Neurology and Developmental Neuroscience; Texas Children's Hospital - Section of Child Neurology

R. D. Clark

Loma Linda University, Medical Center, Department of Pediatrics, Division of Medical Genetics

Ghayda M. Mirzaa

University of Washington - Department of Pediatrics; Seattle Children's Research Institute - Center for Integrative Brain Research

James R. Lupski

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

Hugo Bellen

Baylor College of Medicine - Howard Hughes Medical Institute; Baylor College of Medicine - Department of Molecular and Human Genetics; Texas Children's Hospital - 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

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Abstract

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.

Keywords: VRK1, Par complex, aPKC, L(2)gl, Miranda, Bazooka, Ballchen, brain development, Drosophila, congenital infection, MCPH16

Suggested Citation

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). DEVELOPMENTAL-CELL-D-19-00399. Available at SSRN: https://ssrn.com/abstract=3389483 or http://dx.doi.org/10.2139/ssrn.3389483
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Nichole Link

Baylor University, College of Medicine, Howard Hughes Medical Institute

Houston, TX 77030
United States

Baylor University, College of Medicine, Department of Molecular and Human Genetics

Houston, TX 77030
United States

Texas Children's Hospital - Jan and Dan Duncan Neurologic Research Institute

Houston, TX
United States

Hyunglok Chung

Baylor College of Medicine - Howard Hughes Medical Institute

Houston, TX 77030
United States

Baylor College of Medicine - Department of Molecular and Human Genetics

Houston, TX 77030
United States

Texas Children's Hospital - Jan and Dan Duncan Neurologic Research Institute

Houston, TX
United States

Angad Jolly

Baylor University, College of Medicine, Department of Molecular and Human Genetics

Houston, TX 77030
United States

Baylor University, College of Medicine, MD/PhD Medical Scientist Training Program and MHG Graduate Program

Houston, TX
United States

Marjorie Withers

Baylor University, College of Medicine, Department of Molecular and Human Genetics

Houston, TX 77030
United States

Burak Tepe

Baylor University, College of Medicine, Department of Molecular and Human Genetics

Houston, TX 77030
United States

Texas Children's Hospital - Jan and Dan Duncan Neurologic Research Institute

Houston, TX
United States

Baylor University, College of Medicine, Program in Developmental Biology

Houston, TX 77030
United States

Benjamin R. Arenkiel

Baylor University, College of Medicine, Howard Hughes Medical Institute

Houston, TX 77030
United States

Texas Children's Hospital - Jan and Dan Duncan Neurologic Research Institute

Houston, TX
United States

Baylor University, College of Medicine, Program in Developmental Biology

Houston, TX 77030
United States

Texas Children’s Hospital - Jan and Dan Duncan Neurologic Research Institute

Houston, TX
United States

P. S. Shah

University of California, Davis - Department of Chemical Engineering

Davis, CA
United States

University of California, Davis, College of Biological Sciences, Department of Microbiology and Molecular Genetics

One Shields Ave
Davis, CA 95616
United States

Nevan J. Krogan

University of California, San Francisco (UCSF) - Department of Cellular and Molecular Pharmacology

San Francisco, CA
United States

University of California, San Francisco (UCSF) - Institute for Quantitative Biosciences (QB3)

Third Avenue and Parnassus
San Francisco, CA 94143
United States

Hatip Aydin

Zeynep Kamil Maternity and Children's Training and Research Hospital - Center of Genetics Diagnosis

Istanbul
Turkey

Bilgen B. Geckinli

Marmara University, School of Medicine, Department of Medical Genetics

Istanbul
Turkey

Tulay Tos

Dr. Sami Ulus Research and Training Hospital of Women's and Children's Health and Diseases - Department of Medical Genetics

Ankara
Turkey

Sedat Isikay

Hasan Kalyoncu University, School of Health Sciences, Department of Physiotherapy and Rehabilitation

Gaziantep
Turkey

Beyhan Tuysuz

Istanbul University, Cerrahpasa Faculty of Medicine, Department of Pediatrics

Istanbul
Turkey

Ganesh H. Mochida

Harvard University - Division of Genetics and Genomics

Boston, MA
United States

Harvard University - Department of Pediatrics

Boston, MA
United States

Harvard University - Manton Center for Orphan Disease Research

Boston, MA
United States

Harvard University - Department of Pediatrics

Boston, MA
United States

Massachusetts General Hospital, Department of Neurology, Pediatric Neurology Unit

Boston, MA
United States

A. X. Thomas

Baylor University, College of Medicine, Department of Pediatrics, Section of Neurology and Developmental Neuroscience

Houston, TX
United States

Texas Children's Hospital - Section of Child Neurology

Houston, TX
United States

R. D. Clark

Loma Linda University, Medical Center, Department of Pediatrics, Division of Medical Genetics

Loma Linda, CA
United States

Ghayda M. Mirzaa

University of Washington - Department of Pediatrics

Seattle, WA
United States

Seattle Children's Research Institute - Center for Integrative Brain Research

Seattle, WA
United States

James R. Lupski

Baylor University, College of Medicine, Department of Molecular and Human Genetics

Houston, TX 77030
United States

Baylor University, College of Medicine, Department of Pediatrics

One Baylor Plaza
Houston, TX 77030
United States

Baylor University, College of Medicine, Human Genome Sequencing Center

One Baylor Plaza
Apt 510
Houston, TX 77057
United States

Hugo Bellen (Contact Author)

Baylor College of Medicine - Howard Hughes Medical Institute ( email )

Houston, TX 77030
United States

Baylor College of Medicine - Department of Molecular and Human Genetics ( email )

Houston, TX 77030
United States

Texas Children's Hospital - Jan and Dan Duncan Neurologic Research Institute ( email )

Houston, TX
United States

Baylor University, College of Medicine, MD/PhD Medical Scientist Training Program and MHG Graduate Program ( email )

Houston, TX
United States

Baylor University, College of Medicine, Program in Developmental Biology ( email )

Houston, TX 77030
United States

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