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

Animals Asymmetric Cell Division / physiology Cell Division Cell Polarity / physiology Drosophila melanogaster / metabolism Humans Membrane Proteins / genetics Microcephaly / virology Mutation Neural Stem Cells / metabolism Neurons / cytology Nuclear Proteins / genetics Zika Virus
Ballchen Bazooka L(2)gl MCPH16 Miranda NS4A VRK1 aPKC brain development congenital infection

Journal

Developmental cell
ISSN: 1878-1551
Titre abrégé: Dev Cell
Pays: United States
ID NLM: 101120028

Informations de publication

Date de publication:
16 12 2019
Historique:
received: 13 05 2019
revised: 19 08 2019
accepted: 14 10 2019
pubmed: 19 11 2019
medline: 11 6 2020
entrez: 19 11 2019
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.devcel.2019.10.009 PMID: 31735666 PMC: PMC6917859
pubmed: 31735666
pii: S1534-5807(19)30853-6
doi: 10.1016/j.devcel.2019.10.009
pmc: PMC6917859
mid: NIHMS1545068
pii:
doi:

Substances chimiques

ANKLE2 protein, human 0
Membrane Proteins 0
Nuclear Proteins 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

713-729.e6

Subventions

Organisme : NINDS NIH HHS
ID : F32 NS092270
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK109934
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS078294
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD083092
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG006542
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS105078
Pays : United States
Organisme : NINDS NIH HHS
ID : K08 NS092898
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM067858
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NINDS NIH HHS
ID : U54 NS093793
Pays : United States
Organisme : NIH HHS
ID : R24 OD022005
Pays : United States

Informations de copyright

Copyright © 2019 Elsevier Inc. All rights reserved.

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Auteurs

Nichole Link (N)

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.

Hyunglok Chung (H)

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.

Angad Jolly (A)

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.

Marjorie Withers (M)

Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA.

Burak Tepe (B)

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.

Benjamin R Arenkiel (BR)

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.

Priya S Shah (PS)

Department of Chemical Engineering and Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, CA 95616, USA.

Nevan J Krogan (NJ)

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.

Hatip Aydin (H)

Center of Genetics Diagnosis, Zeynep Kamil Maternity and Children's Training and Research Hospital, Istanbul, Turkey.

Bilgen B Geckinli (BB)

Department of Medical Genetics, Marmara University School of Medicine, Istanbul, Turkey.

Tulay Tos (T)

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

Sedat Isikay (S)

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

Beyhan Tuysuz (B)

Department of Pediatrics, Istanbul University-Cerrahpasa, Medical Faculty, Istanbul, Turkey.

Ganesh H Mochida (GH)

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.

Ajay X Thomas (AX)

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.

Robin D Clark (RD)

Division of Medical Genetics, Department of Pediatrics, Loma Linda University Medical Center, Loma Linda, CA 92354, USA.

Ghayda M Mirzaa (GM)

Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98105, USA.

James R Lupski (JR)

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.

Hugo J Bellen (HJ)

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.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Mutations in ANKLE2, a ZIKA Virus Target,...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › Division cellulaire › Division cellulaire asymétrique › Mutations in ANKLE2, a ZIKA Virus Target,...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › Division cellulaire › Mutations in ANKLE2, a ZIKA Virus Target,...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Polarité de la cellule › Mutations in ANKLE2, a ZIKA Virus Target,...
questionsmedicales.fr › Eucaryotes › Animaux › Invertébrés › Arthropodes › Insectes › Pterygota › Neoptera › Holometabola › Diptera › Drosophilidae › Drosophila › Drosophila melanogaster › Mutations in ANKLE2, a ZIKA Virus Target,...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Mutations in ANKLE2, a ZIKA Virus Target,...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Mutations in ANKLE2, a ZIKA Virus Target,...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Malformations › Malformations du système nerveux › Malformations corticales › Malformations corticales du groupe I › Microcéphalie › Mutations in ANKLE2, a ZIKA Virus Target,...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutations in ANKLE2, a ZIKA Virus Target,...
questionsmedicales.fr › Cellules › Cellules souches › Cellules souches neurales › Mutations in ANKLE2, a ZIKA Virus Target,...
questionsmedicales.fr › Cellules › Neurones › Mutations in ANKLE2, a ZIKA Virus Target,...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines nucléaires › Mutations in ANKLE2, a ZIKA Virus Target,...
questionsmedicales.fr › Virus › Virus à ARN › Virus à ARN à brin positif › Flaviviridae › Flavivirus › Virus Zika › Mutations in ANKLE2, a ZIKA Virus Target,...