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General Information
Name
cancer, neural stem cell, AFDN-SCRIB-related
FlyBase ID
FBhh0000952
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. Asymmetric cell division (ACD), a critical part of the process of stem cell renewal vs. differentiation, has been extensively studied in the context of this system. This report describes a neural stem cell cancer model using the fly genes cno, a scaffold protein involved in organization of adherens junctions, and scrib, a component of the Scribble cell polarity complex that is also involved in organization of adherens junctions. Both Dmel\cno and Dmel\scrib participate in the process of asymmetric cell division, characterized primarily in neural and epithelial tissues. Classical amorphic and hypomorphic mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for both fly genes.

Dmel\cno is orthologous to the human gene AFDN; Dmel\scrib is orthologous to to human SCRIB and LRRC1. The mammalian SCRIB gene has also been characterized as a tumor suppressor. The human genes Hsap\AFDN and Hsap\SCRIB have been introduced into flies, but have not been characterized in the context of this disease model. A wild-type transgene of Hsap\SCRIB exhibits partial heterologous rescue (functional complementation) of homozygous Dmel\scrib loss-of-function phenotypes.

Assessed by generating mutant clones in otherwise wild-type tissue, loss of either cno or scrib alone in neuroblasts of the larval brain fails to produce an overproliferation phenotype. Double-mutant clones, however, do exhibit tumor-like overgrowth, resulting in formation of tumorous masses composed primarily of progenitor cells, with very few differentiated cells. Based on abnormal distribution of markers of asymmetric cell division, it is postulated that the ACD process is severely compromised in the double-mutant clones and that this could account for the increase in progenitor cells.

[updated Jan. 2019 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: cancer, neural stem cell, AFDN-SCRIB-related
OMIM report
Human gene(s) implicated
Symptoms and phenotype
Genetics
Cellular phenotype and pathology
Molecular information

SCRIB is a cytoplasmic multi-modular scaffold protein targeted to epithelial adherens junctions and neuronal presynaptic compartments. SCRIB and its orthologs in vertebrates and invertebrates participate in cell polarization (summary by Nola et al., 2008; pubmed:18716323). [from OMIM:607733; 2017.08.01]

AFDN (afadin) encodes a multi-domain protein involved in signaling and in the organization of homotypic, interneuronal, and heterotypic cell-cell adherens junctions; probably interacts with the E-cadherin-catenin system. [Gene Cards, AFDN; 2019.01.08]

External links
Disease synonyms
Search term: hyperplastic phenotype(s)
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Two to one: 2 human to 1 Drosophila; the second human gene is LRRC1.

Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)
Other mammalian ortholog(s) used
    D. melanogaster Gene Information (2)
    Gene Snapshot
    canoe (cno) encodes a scaffold protein in adherens junctions that is involved in morphogenesis in a variety of tissues. [Date last reviewed: 2019-03-07]
    Gene Groups / Pathways
    Comments on ortholog(s)

    High-scoring ortholog of human AFDN (1 Drosophila to 1 human). Dmel\cno shares 32% identity and 47% similarity with the human gene.

    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Gene Snapshot
    scribble (scrib) encodes a scaffolding protein that is part of the conserved machinery regulating apicobasal polarity. It acts with the products of dlg1 and l(2)gl to distinguish the basolateral domain of epithelial cells and neuroblasts, via reciprocally antagonistic interactions with the aPKC/par-6 complex that impacts vesicle trafficking. The product of scrib also organizes synaptic architecture and is implicated in learning and memory. [Date last reviewed: 2019-03-14]
    Molecular function (GO)
    Gene Groups / Pathways
    Comments on ortholog(s)

    Moderate-scoring ortholog of human SCRIB and LRRC1 (1 Drosophila to 2 human); Dmel\scrib shares 33% identity and 45% similarity with the human SCRIB gene. The human LRRC1 gene encodes a much smaller protein, corresponding to the amino end of SCRIB and Dmel\scrib; it shares 57% identity and 73% similarity with Dmel\scrib within that extent.

    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Other Genes Used: Viral, Bacterial, Synthetic (0)
      Summary of Physical Interactions (29 groups)
      protein-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, peptide massfingerprinting
      two hybrid, anti tag coimmunoprecipitation, autoradiography, anti bait coimmunoprecipitation, western blot, pull down, anti tag western blot
      anti bait coimmunoprecipitation, western blot, pull down, autoradiography
      anti tag coimmunoprecipitation, autoradiography, western blot, two hybrid, anti bait coimmunoprecipitation
      anti bait coimmunoprecipitation, western blot, pull down
      two hybrid, pull down, autoradiography
      anti tag coimmunoprecipitation, anti tag western blot, pull down, western blot
      anti tag coimmunoprecipitation, autoradiography, two hybrid
      anti tag coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, western blot
      pull down, molecular weight estimation by staining
      nuclear magnetic resonance, predetermined participant
      anti tag coimmunoprecipitation, western blot
      protein-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, anti tag western blot
      proximity ligation assay, fluorescence microscopy
      colocalization, fluorescence microscopy, inferred by author, anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation, proximity ligation assay
      proximity ligation assay, fluorescence microscopy
      x-ray crystallography, isothermal titration calorimetry, predetermined participant, anti bait coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, anti tag western blot
      pull down, western blot, anti tag coimmunoprecipitation
      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, anti tag western blot
      pull down, autoradiography
      anti tag coimmunoprecipitation, western blot
      pull down, autoradiography, two hybrid
      Alleles Reported to Model Human Disease (Disease Ontology) (10 alleles)
      Models Based on Experimental Evidence ( 0 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 1 )
      Allele
      Disease
      Interaction
      References
      Models Based on Experimental Evidence ( 6 )
      Modifiers Based on Experimental Evidence ( 6 )
      Allele
      Disease
      Interaction
      References
      model of  carcinoma
      is ameliorated by licGD7546
      is ameliorated by licJF01433
      Models Based on Experimental Evidence ( 0 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 1 )
      Allele
      Disease
      Interaction
      References
      Models Based on Experimental Evidence ( 1 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 0 )
      Allele
      Disease
      Interaction
      References
      Alleles Representing Disease-Implicated Variants
      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
      amorphic allele - genetic evidence
      Delta2-3 transposase
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      References (6)