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General Information
Name
cancer, neural stem cell, LLGL-related
FlyBase ID
FBhh0000771
Disease Ontology Term
Parent Disease
OMIM
Overview

The role of neuroblasts in the development of the Drosophila larval/adult brain has served as a model for the role of adult neural stem cells in normal neural development and in tumor formation. Loss-of-function mutations that affect normal neuroblast differentiation in Drosophila often result in conspicuous phenotypes of overproliferation and tumorous expansion of the brain at the larval stage. Based on this phenotype, a number of genes impacting this process in flies have been identified. This report describes a human disease model using the fly gene l(2)gl. In human, there are two genes orthologous to Dmel\l(2)gl, the cortical cytoskeletal proteins LLGL1 and LLGL2. Classical amorphic and hypomorphic mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\l(2)gl.

A tagged wild-type transgene of human Hsap\LLGL1 has been introduced into flies; partial heterologous rescue (functional complementation) of the homozygous Dmel\l(2)gl lethal phenotype is observed.

Animals homozygous for loss-of-function mutations of Dmel\l(2)gl typically die during the larval stage and exhibit abnormal overproliferation of tissues, including in the brain, imaginal discs, and hematopoietic organs; cell-polarity defects are observed. Using a tissue transplant assay for neoplastic capacity, discs of larvae transplanted into wild-type adult female abdomens form large contained tumors; transplanted optic primordia from larval brains form invasive neuroblastomas, which grow rapidly, killing the host within 7-14 days; they can be serially cultured in adult abdomens. Multiple physical and many genetic interactions for Dmel\l(2)gl have been described; see below and in the gene report for l(2)gl.

See related human disease model reports: human disease models for epithelial cancers related to the LLGL gene (FBhh0000591, FBhh0000590, FBhh0000588) and human disease models for malignant glioma (FBhh0000399, FBhh0000401, FBhh0000403, FBhh0000404, FBhh0000668).

[updated Mar. 2018 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: cancer, neural stem cell, LLGL-related
OMIM report
Human gene(s) implicated
Symptoms and phenotype

Neural stem cells have the ability to self-renew and give rise to neurons and glial cells. In Drosophila, the role and regulation of neural stem cells (neuroblasts) at multiple stages has been studied extensively. The study of neuroblasts in the development of the larval/adult brain has served as a model for the role of adult stem cells in normal neural development and in tumor formation. Asymmetric cell division, a critical part of the process of stem cell renewal vs. differentiation, has been studied in the context of this system.

Genetics
Cellular phenotype and pathology
Molecular information

LLGL1 and LLGL2 encode cortical cytoskeleton proteins found in a complex involved in maintaining cell polarity and epithelial integrity, the Scribble Cell Polarity Complex. This complex plays a role in the initial phase of the establishment of epithelial cell polarity; it is involved in the regulation of mitotic spindle orientation, proliferation, differentiation, and tissue organization of neuroepithelial cells. [Gene Cards, LLGL1, LLGL2; 2017.08.01]

External links
Disease synonyms
malignant glioma, LLGL-related
cancer, neuroblast-derived, LLGL-related
brain cancer, LLGL-related
Search term: metastatic phenotype(s)
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one: 2 human to 1 Drosophila; the second human gene is LLGL1.

Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one: 2 human to 1 Drosophila; the second human gene is LLGL2.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    lethal (2) giant larvae (l(2)gl) encodes a tumor suppressor protein that regulates cell polarity and asymmetric cell division. It acts on the basolateral side of epithelial cells, antagonizing the activity of apical complex proteins encoded by baz, par-6 and aPKC. [Date last reviewed: 2019-09-26]
    Gene Groups / Pathways
    Comments on ortholog(s)

    Moderate- to high-scoring ortholog of human LLGL1 and LLGL2 (1 Drosophila to 2 human). Dmel\l(2)gl shares 34-36% identity and 51-54% similarity with the human genes.

    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Synthetic Gene(s) Used (0)
    Summary of Physical Interactions (13 groups)
    protein-protein
    Interacting group
    Assay
    References
    anti tag coimmunoprecipitation, anti tag western blot
    anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based
    anti tag coimmunoprecipitation, western blot
    anti tag coimmunoprecipitation, western blot
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, western blot
    anti tag coimmunoprecipitation, western blot
    anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation
    anti tag coimmunoprecipitation, peptide massfingerprinting, anti bait coimmunoprecipitation, western blot, pull down, anti tag western blot, experimental knowledge based, autoradiography
    proximity ligation assay, fluorescence microscopy, anti tag coimmunoprecipitation, anti tag western blot, pull down, Identification by mass spectrometry
    anti tag coimmunoprecipitation, anti tag western blot
    anti tag coimmunoprecipitation, anti tag western blot
    Alleles Reported to Model Human Disease (Disease Ontology) (0 alleles)
    Genetic Tools, Stocks and Reagents
    Sources of Stocks
    Contact lab of origin for a reagent not available from a public stock center.
    Bloomington Stock Center Disease Page
    Selected mammalian transgenes
    Allele
    Transgene
    Publicly Available Stocks
    Selected Drosophila transgenes
    Allele
    Transgene
    Publicly Available Stocks
    RNAi constructs available
    Allele
    Transgene
    Publicly Available Stocks
    Selected Drosophila classical alleles
    Allele
    Allele class
    Mutagen
    Publicly Available Stocks
    loss of function allele
    natural population
    amorphic allele - genetic evidence
    spontaneous
    spontaneous
    amorphic allele - molecular evidence
    ends-out gene targeting
    References (13)