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

Link, Nichole; Chung, Hyunglok; Jolly, Angad; Withers, Marjorie; Tepe, Burak; Arenkiel, Benjamin R.; Shah, Priya S.; Krogan, Nevan J.; Aydın, Hatip; Geçkinli, Bilgen Bilge; Tos, Tülay; Işıkay, Sedat; Tüysüz, Beyhan; Mochida, Ganesh H.; Thomas, Ann Mary; Clark, Robin D.; Mirzaa, Ghayda; Lupski, James R.; Bellen, Hugo J.

doi:10.1016/j.devcel.2019.10.009

Cited by 79 publications

(119 citation statements)

References 111 publications

Supporting

Mentioning

108

Contrasting

Order By: Relevance

“…To verify that ANKLE2 was associated with human microcephaly, human wild-type and variant ANKLE2 cDNAs were expressed in Drosophila mutant for Ankle2. Wild-type human ANKLE2 rescued both lethality and brain size but the variants associated with human microcephaly did not, indicating that ANKLE2 mutations in both Drosophila and humans cause reduced brain size (Link et al, 2019). These results confirmed that ANKLE2 function is conserved, and that variants in ANKLE2 lead to primary microcephaly (MCPH16).…”

Section: Drosophila As a Model For Diagnosing And Investigating Causementioning

confidence: 68%

“…Experiments using Drosophila have also helped to solve a case of a single individual affected by severe microcephaly; follow-up studies then led to the unraveling of the pathogenic mechanisms and to the discovery of many new genes associated with microcephaly in humans (Link et al, 2019;Yamamoto et al, 2014). A mutation in Ankle2 was recovered from a large mutagenesis screen in Drosophila designed to identify novel mutations associated with neurodevelopmental or neurodegenerative phenotypes (Yamamoto et al, 2014).…”

Section: Drosophila As a Model For Diagnosing And Investigating Causementioning

confidence: 99%

“…Additional studies showed that Ankle2 interacts with a kinase called Ballchen (VRK1 in humans) to regulate the asymmetric division of Drosophila neuroblasts (Link et al, 2019). It was also noted that the localization of key polarity proteins, including the PAR complex proteins aPKC, Par3 and Par6, was disrupted in dividing Ankle2 mutant neuroblasts.…”

Section: Drosophila As a Model For Diagnosing And Investigating Causementioning

confidence: 99%

“…Indeed, research on Drosophila in the Model Organism Screening Center (MOSC) of the Undiagnosed Diseases Network (see below) and in collaboration with other human geneticists has provided diagnoses for more than 25 rare human genetic diseases in less than 4 years (Bellen et al, 2019;Wangler et al, 2017a;2017b). These include diseases caused by proteins associated with different organelles, such as mitochondria (Chao et al, 2017;Harel et al, 2016;Liu et al, 2017;Oláhová et al, 2018;Yoon et al, 2017), peroxisomes (Chao et al, 2016;Chung et al, 2020;Luo et al, 2017;Wangler et al, 2017b), lysosomes (Sȩntürk et al, 2019) and endosomes (Lin et al, 2018), as well as numerous developmental disorders (Ansar et al, 2018a;Ansar et al, 2018b;Link et al, 2019;Marcogliese et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Using Drosophila to drive the diagnosis and understand the mechanisms of rare human diseases

Link

Bellen

2020

Development

Self Cite

View full text Add to dashboard Cite

Next-generation sequencing has greatly accelerated the discovery of rare human genetic diseases. Nearly 45% of patients have variants associated with known diseases but the unsolved cases remain a conundrum. Moreover, causative mutations can be difficult to pinpoint because variants frequently map to genes with no previous disease associations and, often, only one or a few patients with variants in the same gene are identified. Model organisms, such as Drosophila, can help to identify and characterize these new disease-causing genes. Importantly, Drosophila allow quick and sophisticated genetic manipulations, permit functional testing of human variants, enable the characterization of pathogenic mechanisms and are amenable to drug tests. In this Spotlight, focusing on microcephaly as a case study, we highlight how studies of human genes in Drosophila have aided our understanding of human genetic disorders, allowing the identification of new genes in well-established signaling pathways.

show abstract

Section: Drosophila As a Model For Diagnosing And Investigating Causementioning

confidence: 68%

Section: Drosophila As a Model For Diagnosing And Investigating Causementioning

confidence: 99%

Section: Drosophila As a Model For Diagnosing And Investigating Causementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Using Drosophila to drive the diagnosis and understand the mechanisms of rare human diseases

Link

Bellen

2020

Development

Self Cite

View full text Add to dashboard Cite

show abstract

“…Overexpression of human cytomegalovirus immediate-early genes in Drosophila embryos results in abnormal embryonic development associated with disrupted adherens junctions (Steinberg et al, 2008). Recently, there have also been efforts to dissect host-ZIKV interactions using Drosophila as the model organism (Harsh et al, 2018;Link et al, 2019;Liu et al, 2018). Findings from these studies indicate that Drosophila can be a reliable model to analyze ZIKV tropism.…”

Section: Introductionmentioning

confidence: 99%

Zika virus non-structural protein NS4A restricts eye growth inDrosophilathrough regulation of JAK/STAT signaling

Harsh

Kenney

et al. 2020

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

To gain a comprehensive view of the changes in host gene expression underlying Zika virus (ZIKV) pathogenesis, we performed whole-genome RNA sequencing (RNA-seq) of ZIKV-infected Drosophila adult flies. RNA-seq analysis revealed that ZIKV infection alters several and diverse biological processes, including stress, locomotion, lipid metabolism, imaginal disc morphogenesis and regulation of JAK/STAT signaling. To explore the interaction between ZIKV infection and JAK/STAT signaling regulation, we generated genetic constructs overexpressing ZIKVspecific non-structural proteins NS2A, NS2B, NS4A and NS4B. We found that ectopic expression of non-structural proteins in the developing Drosophila eye significantly restricts growth of the larval and adult eye and correlates with considerable repression of the in vivo JAK/STAT reporter, 10XStat92E-GFP. At the cellular level, eye growth defects are associated with reduced rate of proliferation without affecting the overall rate of apoptosis. In addition, ZIKV NS4A genetically interacts with the JAK/STAT signaling components; co-expression of NS4A along with the dominant-negative form of domeless or StatRNAi results in aggravated reduction in eye size, while co-expression of NS4A in HopTuml (also known as hop Tum ) mutant background partially rescues the hop-induced eye overgrowth phenotype. The function of ZIKV NS4A in regulating growth is maintained in the wing, where ZIKV NS4A overexpression in the pouch domain results in reduced growth linked with diminished expression of Notch targets, Wingless (Wg) and Cut, and the Notch reporter, NRE-GFP. Thus, our study provides evidence that ZIKV infection in Drosophila results in restricted growth of the developing eye and wing, wherein eye phenotype is induced through regulation of JAK/ STAT signaling, whereas restricted wing growth is induced through regulation of Notch signaling. The interaction of ZIKV non-structural proteins with the conserved host signaling pathways further advance our understanding of ZIKV-induced pathogenesis.This article has an associated First Person interview with the first author of the paper.

show abstract

ANKLE2‐related microcephaly: A variable microcephaly syndrome resembling Zika infection

Thomas

Link

Robak

et al. 2022

Ann Clin Transl Neurol

Self Cite

View full text Add to dashboard Cite

Objective: This study delineates the clinical and molecular spectrum of ANKLE2-related microcephaly (MIC), as well as highlights shared pathological mechanisms between ANKLE2 and the Zika virus. Methods: We identified 12 individuals with MIC and variants in ANKLE2 with a broad range of features. Probands underwent thorough phenotypic evaluations, developmental assessments, and anthropometric measurements. Brain imaging studies were systematically reviewed for developmental abnormalities. We functionally interrogated a subset of identified ANKLE2 variants in Drosophila melanogaster. Results: All individuals had MIC (z-score ≤ À3), including nine with congenital MIC. We identified a broad range of brain abnormalities including simplified cortical gyral pattern, full or partial callosal agenesis, increased extra-axial spaces, hypomyelination, cerebellar vermis hypoplasia, and enlarged cisterna magna. All probands had developmental delays in at least one domain, with speech and language delays being the most common. Six probands had skin findings 1276

show abstract

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

Cited by 79 publications

References 111 publications

Using Drosophila to drive the diagnosis and understand the mechanisms of rare human diseases

Using Drosophila to drive the diagnosis and understand the mechanisms of rare human diseases

Zika virus non-structural protein NS4A restricts eye growth inDrosophilathrough regulation of JAK/STAT signaling

ANKLE2‐related microcephaly: A variable microcephaly syndrome resembling Zika infection

Contact Info

Product

Resources

About