Human Disease Model Report: cancer, neural stem cell, HES (bHLH TF)-related

General Information

Name

cancer, neural stem cell, HES (bHLH TF)-related

FlyBase ID

FBhh0000783

Disease Ontology Term

central nervous system cancer

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. This report describes neural stem cell cancer models using the fly genes dpn, E(spl)mγ-HLH, and E(spl)m8-HLH, basic helix-loop-helix (bHLH) transcription factors. There are multiple bHLH transcription factors in both human and fly; Dmel\dpn is most closely related to human HES1, HES2, and HES4 (most similar to HES1); E(spl)mγ-HLH is most similar to HES2 and HES6; E(spl)m8-HLH is most similar to HES2.

A UAS construct of a tagged human Hsap\HES4 gene has been introduced into flies, but has not been characterized in the context of this disease model.

Initial studies used Dmel\dpn; classical amorphic and hypomorphic mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for this gene. Animals homozygous for a severe loss-of-function mutation of Dmel\dpn rarely survive to adulthood; type II neuroblasts are completely absent in the brains of late third instar larvae. Using a GAL4 driver for the neuroblast lineage, overexpression of dpn results in dramatic overproliferation in the brain lobes and ventral nerve cord of third instar larvae.

Subsequent studies have used overexpression of combinations of two HES-related genes: E(spl)mγ-HLH with E(spl)m8-HLH or E(spl)mγ-HLH with dpn (these combinations exhibit strong DNA binding as heterodimers in vitro). Overexpression of either combination in larval neuroblasts results in hyperplasias in the larval central nervous system, which can progress to malignant tumors after allografting to adult hosts.

[updated Sep. 2021 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: cancer, neural stem cell, HES (bHLH TF)-related

OMIM report

Human gene(s) implicated

Symptoms and phenotype

Genetics

Cellular phenotype and pathology

Molecular information

Basic helix-loop-helix proteins comprise large gene families in both human and Drosophila (https://www.genenames.org/cgi-bin/genefamilies/set/420; http://flybase.org/reports/FBgg0000727.html).

(FlyBase Curators, 2013-)

External links

COSMIC gene: HES4
COSMIC gene: HES1
COSMIC gene: HES2
COSMIC gene: HES6
Gene2Function (human gene): HES1
Gene2Function (human gene): HES4
Gene2Function (human gene): HES2
Gene2Function (human gene): HES6
Gene Cards: HES1
Gene Cards: HES4
Gene Cards: HES2
Gene Cards: HES6
MedlinePlus (gene): HES4
MedlinePlus (gene): HES1
MedlinePlus (gene): HES2
MedlinePlus (gene): HES6
MARRVEL (human gene): HES1
MARRVEL (human gene): HES4
MARRVEL (human gene): HES2
MARRVEL (human gene): HES6
NCBI (Entrez) gene: HES1; hes family bHLH transcription factor 1
NCBI (Entrez) gene: HES4; hes family bHLH transcription factor 4
NCBI (Entrez) gene: HES2; hes family bHLH transcription factor 2
NCBI (Entrez) gene: HES6; hes family bHLH transcription factor 6

Disease synonyms

brain cancer, HES-related

brain tumor, HES-related

cancer, neuroblast-derived, HES-related

Related Diseases

Related human health report(s)

Ortholog Information

Human gene(s) in FlyBase

Hsap\HES4

Human gene (HGNC)

Symbol / Name

HES1; hes family bHLH transcription factor 1

D. melanogaster ortholog (based on DIOPT)

Dmel\dpn

(DIOPT, 2013-)

Dmel\hry

(DIOPT, 2013-)

Comments on ortholog(s)

Many to many: many homologous genes in both species; Dmel\dpn is most closely related to human HES1.

Human gene (HGNC)

Symbol / Name

HES4; hes family bHLH transcription factor 4

D. melanogaster ortholog (based on DIOPT)

Dmel\hry

(DIOPT, 2013-)

Dmel\dpn

(DIOPT, 2013-)

Comments on ortholog(s)

Many to many: many homologous genes in both species.

Human gene (HGNC)

Symbol / Name

HES2; hes family bHLH transcription factor 2

D. melanogaster ortholog (based on DIOPT)

Dmel\E(spl)m5-HLH

(DIOPT, 2013-)

Dmel\E(spl)mδ-HLH

(DIOPT, 2013-)

Dmel\E(spl)m8-HLH

(DIOPT, 2013-)

Comments on ortholog(s)

Many to many: many homologous genes in both species.

Human gene (HGNC)

Symbol / Name

HES6; hes family bHLH transcription factor 6

D. melanogaster ortholog (based on DIOPT)

Dmel\E(spl)m3-HLH

(DIOPT, 2013-)

Dmel\E(spl)mγ-HLH

(DIOPT, 2013-)

Comments on ortholog(s)

Many to many: many homologous genes in both species.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (3)

Dmel\dpn

Gene Snapshot

Contributions welcome

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

BHLH

Comments on ortholog(s)

Moderate-scoring ortholog of human HES1, HES2, and HES4; most closely related to HES1 (many homologous genes in both species). Dmel\dpn shares 40% identity and 56% similarity with the human HES1 gene.

Orthologs and Alignments from DRSC

DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans

H. sapiens (Human)

Dmel\E(spl)m8-HLH

Gene Snapshot

Contributions welcome

Molecular function (GO)

Cellular component (GO)

nucleus

Gene Groups / Pathways

ESPL-C
BHLH

Comments on ortholog(s)

Moderate-scoring ortholog of human HES2 (many homologous genes in both species).

Orthologs and Alignments from DRSC

DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans

H. sapiens (Human)

Dmel\E(spl)mγ-HLH

Gene Snapshot

Contributions welcome

Molecular function (GO)

Cellular component (GO)

nucleus

Gene Groups / Pathways

ESPL-C
BHLH

Comments on ortholog(s)

Moderate-scoring ortholog of human HES6 and HES2 (many homologous genes in both species).

Orthologs and Alignments from DRSC

DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans

H. sapiens (Human)

Other Genes Used: Viral, Bacterial, Synthetic (0)

Summary of Physical Interactions (66 groups)

dpn

protein-protein

Interacting group

Assay

References

dpn

two hybrid, anti tag coimmunoprecipitation, anti tag western blot

(Komori et al., 2018, Liu and Belote, 1995)

dpn - CHOp24

anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based

(Rhee et al., 2014)

dpn - da

two hybrid

(Liu and Belote, 1995)

dpn - Df31

anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based

(Rhee et al., 2014)

dpn - dgrn

pull down, autoradiography

(Barry et al., 2011)

dpn - E(spl)m8-HLH

electrophoretic mobility shift assay, electrophoretic mobility supershift assay, autoradiography

(Zacharioudaki et al., 2012)

dpn - E(spl)mγ-HLH

electrophoretic mobility shift assay, electrophoretic mobility supershift assay, autoradiography, anti tag coimmunoprecipitation, anti tag western blot

(Komori et al., 2018, Zacharioudaki et al., 2012)

dpn - GATAe

two hybrid array

(Shokri et al., 2019)

dpn - gro

two hybrid, pull down, autoradiography, inferred by curator

(Jennings et al., 2006, Poortinga et al., 1998, Paroush et al., 1994)

dpn - Hr78

two hybrid array

(Shokri et al., 2019)

dpn - hry

pull down, autoradiography

(Secombe and Parkhurst, 2004)

dpn - insb

anti tag coimmunoprecipitation, anti tag western blot, western blot

(Komori et al., 2018)

dpn - Sirt1

pull down, autoradiography

(Rosenberg and Parkhurst, 2002)

dpn - sisA

two hybrid

(Liu and Belote, 1995)

RNA-protein

Interacting group

Assay

References

dpn - brat

electrophoretic mobility shift assay, autoradiography, anti tag coimmunoprecipitation, primer specific pcr

(Reichardt et al., 2018, Loedige et al., 2015)

E(spl)m8-HLH

protein-protein

Interacting group

Assay

References

E(spl)m8-HLH

two hybrid

(Eastwood et al., 2011, Alifragis et al., 1997)

E(spl)m8-HLH - ato

two hybrid

(Eastwood et al., 2011)

E(spl)m8-HLH - βTub85D

experimental knowledge based

(Guruharsha et al., 2011)

E(spl)m8-HLH - CCDC53

anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based

(Rhee et al., 2014)

E(spl)m8-HLH - CG1792

two hybrid array

(Shokri et al., 2019)

E(spl)m8-HLH - CG31955

two hybrid array

(Shokri et al., 2019)

E(spl)m8-HLH - CG32219

experimental knowledge based

(Guruharsha et al., 2011)

E(spl)m8-HLH - CkIIα

two hybrid

(Eastwood et al., 2011, Karandikar et al., 2004)

E(spl)m8-HLH - CtBP

two hybrid array

(Shokri et al., 2019)

E(spl)m8-HLH - da

two hybrid, one hybrid

(Zarifi et al., 2012, Alifragis et al., 1997)

E(spl)m8-HLH - dgrn

pull down, autoradiography

(Barry et al., 2011)

E(spl)m8-HLH - dpn

electrophoretic mobility shift assay, electrophoretic mobility supershift assay, autoradiography

(Zacharioudaki et al., 2012)

E(spl)m8-HLH - E(spl)m5-HLH

two hybrid

(Alifragis et al., 1997)

E(spl)m8-HLH - E(spl)m7-HLH

two hybrid

(Alifragis et al., 1997)

E(spl)m8-HLH - E(spl)mβ-HLH

two hybrid

(Alifragis et al., 1997)

E(spl)m8-HLH - E(spl)mδ-HLH

two hybrid

(Alifragis et al., 1997)

E(spl)m8-HLH - E(spl)mγ-HLH

two hybrid

(Zarifi et al., 2012, Alifragis et al., 1997)

E(spl)m8-HLH - esg

two hybrid array

(Shokri et al., 2019)

E(spl)m8-HLH - Fbp2

experimental knowledge based

(Guruharsha et al., 2011)

E(spl)m8-HLH - gro

two hybrid, pull down, autoradiography, inferred by curator, anti tag coimmunoprecipitation, western blot

(Kiparaki et al., 2015, Eastwood et al., 2011, Kahali et al., 2010, Jennings et al., 2006, Karandikar et al., 2004, Poortinga et al., 1998, Alifragis et al., 1997, Paroush et al., 1994)

E(spl)m8-HLH - Hr78

two hybrid array

(Shokri et al., 2019)

E(spl)m8-HLH - hry

pull down, autoradiography

(Secombe and Parkhurst, 2004)

E(spl)m8-HLH - kn

two hybrid array

(Shokri et al., 2019)

E(spl)m8-HLH - Rab7

experimental knowledge based

(Guruharsha et al., 2011)

E(spl)m8-HLH - Rab14

experimental knowledge based

(Guruharsha et al., 2011)

E(spl)m8-HLH - Rel

two hybrid array

(Shokri et al., 2019)

E(spl)m8-HLH - RpS15Ab

experimental knowledge based

(Guruharsha et al., 2011)

E(spl)m8-HLH - slmb

experimental knowledge based

(Guruharsha et al., 2011)

E(spl)mγ-HLH

RNA-RNA

Interacting group

Assay

References

E(spl)mγ-HLH - mir-4

fluorescence technology

(Lai et al., 2005)

E(spl)mγ-HLH - mir-7

fluorescence technology

(Lai et al., 2005)

E(spl)mγ-HLH - mir-79

fluorescence technology

(Lai et al., 2005)

protein-protein

Interacting group

Assay

References

E(spl)mγ-HLH

two hybrid

(Alifragis et al., 1997)

E(spl)mγ-HLH - ac

two hybrid

(Alifragis et al., 1997)

E(spl)mγ-HLH - ase

two hybrid

(Alifragis et al., 1997)

E(spl)mγ-HLH - CG8388

two hybrid array

(Shokri et al., 2019)

E(spl)mγ-HLH - da

two hybrid, one hybrid

(Zarifi et al., 2012, Alifragis et al., 1997)

E(spl)mγ-HLH - dgrn

pull down, autoradiography

(Barry et al., 2011)

E(spl)mγ-HLH - dpn

electrophoretic mobility shift assay, electrophoretic mobility supershift assay, autoradiography, anti tag coimmunoprecipitation, anti tag western blot

(Komori et al., 2018, Zacharioudaki et al., 2012)

E(spl)mγ-HLH - E(spl)m3-HLH

two hybrid

(Alifragis et al., 1997)

E(spl)mγ-HLH - E(spl)m5-HLH

two hybrid

(Alifragis et al., 1997)

E(spl)mγ-HLH - E(spl)m7-HLH

two hybrid

(Alifragis et al., 1997)

E(spl)mγ-HLH - E(spl)m8-HLH

two hybrid

(Zarifi et al., 2012, Alifragis et al., 1997)

E(spl)mγ-HLH - E(spl)mβ-HLH

two hybrid

(Alifragis et al., 1997)

E(spl)mγ-HLH - E(spl)mδ-HLH

two hybrid

(Alifragis et al., 1997)

E(spl)mγ-HLH - Ets65A

two hybrid array

(Shokri et al., 2019)

E(spl)mγ-HLH - gro

two hybrid, pull down, autoradiography, inferred by curator

(Jennings et al., 2006, Poortinga et al., 1998, Alifragis et al., 1997)

E(spl)mγ-HLH - Gsc

two hybrid

(Hu et al., 2017.6.13)

E(spl)mγ-HLH - Hey

two hybrid array

(Shokri et al., 2019)

E(spl)mγ-HLH - insb

two hybrid, anti tag coimmunoprecipitation, anti tag western blot

(Komori et al., 2018, Hu et al., 2017.6.13)

E(spl)mγ-HLH - Rel

two hybrid array

(Shokri et al., 2019)

E(spl)mγ-HLH - sc

one hybrid, two hybrid

(Zarifi et al., 2012, Poortinga et al., 1998, Alifragis et al., 1997)

E(spl)mγ-HLH - sina

two hybrid

(Hu et al., 2017.6.13)

E(spl)mγ-HLH - Ubx

bimolecular fluorescence complementation, fluorescence microscopy

(Bischof et al., 2018)

E(spl)mγ-HLH - vnd

two hybrid array

(Shokri et al., 2019)

Alleles Reported to Model Human Disease (Disease Ontology) (9 alleles)

dpn

Models Based on Experimental Evidence ( 3 )

Allele

Disease

Evidence

References

dpn^UAS.cWa

model of brain cancer

CEA

(Huang et al., 2015)

dpn^UAS.cUa

model of brain cancer

CEA

(Morrissy et al., 2016)

model of central nervous system cancer

CEA

(Francisco et al., 2020)

dpn^UAS.Tag:HA

model of central nervous system cancer

CEA with E(spl)m8-HLH^UAS.Tag:HA

(Magadi et al., 2020)

Modifiers Based on Experimental Evidence ( 4 )

Allele

Disease

Interaction

References

dpn^UAS.cWa

model of brain cancer

is ameliorated by eag^DN.EKI.UAS

(Huang et al., 2015)

is ameliorated by eag¹

(Huang et al., 2015)

is NOT ameliorated by Sh¹⁴

(Huang et al., 2015)

dpn^HMC03154

exacerbates atypical teratoid rhabdoid tumor

modeled by Snr1^KK101602

(Tegeder et al., 2019)

dpn^UAS.cUa

model of brain cancer

is ameliorated by p53^DN.UAS.cUa

(Morrissy et al., 2016)

model of central nervous system cancer

is ameliorated by Clic^EY04209

(Francisco et al., 2020)

is ameliorated by Clic^G0472

(Francisco et al., 2020)

is ameliorated by Clic^KK101604

(Francisco et al., 2020)

is ameliorated by eag^GD3363

(Francisco et al., 2020)

dpn^GFP.FPTB

ameliorates Huntington's disease

modeled by Hsap\HTT^{128Q.1-231.UAS}

(Onur et al., 2021)

E(spl)m8-HLH

Models Based on Experimental Evidence ( 1 )

Allele

Disease

Evidence

References

E(spl)m8-HLH^UAS.Tag:HA

model of central nervous system cancer

CEA with E(spl)mγ-HLH^UAS.Tag:HA

(Magadi et al., 2020)

CEA with dpn^UAS.Tag:HA

(Magadi et al., 2020)

Modifiers Based on Experimental Evidence ( 0 )

Allele

Disease

Interaction

References

E(spl)mγ-HLH

Models Based on Experimental Evidence ( 3 )

Allele

Disease

Evidence

References

E(spl)mγ-HLH^GFP

model of central nervous system cancer

CEA

(Voutyraki et al., 2022)

E(spl)mγ-HLH^UAS.cLa

model of central nervous system cancer

CEA

(Zacharioudaki et al., 2016)

E(spl)mγ-HLH^UAS.Tag:HA

model of central nervous system cancer

CEA with E(spl)m8-HLH^UAS.Tag:HA

(Magadi et al., 2020)

CEA

(Voutyraki et al., 2022)

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

Related mammalian, viral, bacterial, or synthetic transgenes

Allele

Transgene

Publicly Available Stocks

Hsap\HES4^UAS.Tag:HA

PBac{UAS-hHES4.HA}

y¹ w^*; PBac{UAS-hHES4.HA}VK00037/SM6a

Selected Drosophila transgenes

Allele

Transgene

Publicly Available Stocks

E(spl)mγ-HLH^UAS.Tag:HA

P{UAS-E(spl)mgamma-HLH.HA}

E(spl)mγ-HLH^UAS.cLa

P{UAS-E(spl)mgamma-HLH.L}

E(spl)mγ-HLH^GFP

P{E(spl)mgamma-HLH-GFP}

E(spl)m8-HLH^UAS.Tag:HA

P{UAS-E(spl)m8-HLH.HA}

w¹¹¹⁸; PBac{dpn-GFP.FPTB}VK00033

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

E(spl)mγ-HLH^GD4459

P{GD4459}

w¹¹¹⁸; P{GD4459}v10950/TM3

E(spl)mγ-HLH^JF02000

P{TRiP.JF02000}

y¹ v¹; P{TRiP.JF02000}attP2

E(spl)mγ-HLH^NIG.8333R

P{NIG.8333R}

P{NIG.8333R}1

E(spl)mγ-HLH^HMC03315

P{TRiP.HMC03315}

y¹ sc^* v¹ sev²¹; P{TRiP.HMC03315}attP2

E(spl)m8-HLH^GD4447

P{GD4447}

w¹¹¹⁸; P{GD4447}v37685

E(spl)m8-HLH^JF02096

P{TRiP.JF02096}

y¹ v¹; P{TRiP.JF02096}attP2

E(spl)m8-HLH^KK103719

P{KK103719}

P{KK103719}VIE-260B

E(spl)m8-HLH^NIG.8365R

y¹ v¹; P{TRiP.JF02094}attP2

y¹ v¹; P{TRiP.HMC03154}attP2

dpn^VSH330362

P{VSH330362}

P{VSH330362}attP40

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

E(spl)m8-HLH^rv32

loss of function allele

X ray

E(spl)m8-HLH^rv28

loss of function allele

X ray

dpn¹

amorphic allele - genetic evidence

P-element activity

dpn³

loss of function allele

gamma ray

dpn⁶

loss of function allele

gamma ray

dpn⁴

loss of function allele

gamma ray

dpn⁵

loss of function allele

gamma ray

References (8)

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