Human Disease Model Report: alcohol, response to, F-actin turnover-related

General Information

Name

alcohol, response to, F-actin turnover-related

FlyBase ID

FBhh0001189

Disease Ontology Term

alcohol use disorder

Parent Disease

OMIM

Overview

This report describes characterization of the fly alcohol response using the Drosophila genes Rac1 and tsr, which are the Drosophila orthologs of multiple human genes in the RAC family (small GTPases) and the cofilin family (actin remodelers).

Multiple orthologs exist for both fly Rac1 (Hsap\RAC1, Hsap\RAC2) and tsr (Hsap\DSTN, Hsap\CFL2), and at least one human ortholog for each has been introduced to Drosophila. These genes have been linked to other diseases: Hsap\RAC1 has been associated with intellectual disability, autosomal dominant 48 (MIM:617751), Hsap\RAC2 has been associated with neutrophil immunodeficiency syndrome (MIM:608203), and Hsap\CFL2 has been associated with nemaline myopathy 7 (MIM:610687).

Expression of either dominant-negative Rac1 or constitutively active tsr in the mushroom body quickly causes preference for ethanol in naive flies (experience-dependent alcohol preference, EDAP). Both of these mutations cause increased F-actin turnover, suggesting that increased F-actin dynamics enhances the acquisition of alcohol preference.

Knockdown of ics, a negative regulator of Rac1, has been shown to confer resistance to ethanol-induced sedation, and ics-null flies fail to acquire a preference for alcohol (FBhh0000699).

[updated Feb 2020 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: alcohol, response to, F-actin turnover-related

OMIM report

Human gene(s) implicated

Symptoms and phenotype

Genetics

Cellular phenotype and pathology

Molecular information

Rac1 acts by controlling actin dynamics at the growth cone and leading edge on immature neurons, through actin filament polymerization/disassembly, acto-myosin contractility and engagement of intracellular adhesion and anchoring mechanisms via regulation of actin-binding proteins (from Zamboni et al. 2018, pubmed:29740022). Actin filament networks in cells undergo dynamic assembly, disassembly, and reorganization, exchanging subunits with a pool of cytoplasmic actin monomers that needs to be continuously regenerated. The members of actin-depolymerizing factor (ADF)/cofilin family proteins are the most conserved and essential proteins accelerating filament disassembly in cells (from Wioland et al. 2017, pubmed:28625781).

(FlyBase Curators, 2013-)

External links

Gene2Function (human gene): 5879
Gene2Function (human gene): 5880
Gene2Function (human gene): 11034
Gene2Function (human gene): CFL2
Gene2Function (human gene): RAC1
Gene2Function (human gene): RAC2
Gene2Function (human gene): DSTN
Gene2Function (human gene): CFL2
Gene Cards: RAC1
Gene Cards: RAC2
Gene Cards: DSTN
Gene Cards: CFL2
MedlinePlus (condition): Alcohol use disorder
MedlinePlus (gene): CFL2
MedlinePlus (gene): DSTN
MedlinePlus (gene): RAC2
MedlinePlus (gene): RAC1
MARRVEL (human gene): RAC1
MARRVEL (human gene): RAC2
MARRVEL (human gene): DSTN
MARRVEL (human gene): CFL2
NCBI (Entrez) gene: RAC1; Rac family small GTPase 1
NCBI (Entrez) gene: RAC2; Rac family small GTPase 2
NCBI (Entrez) gene: DSTN; destrin, actin depolymerizing factor
NCBI (Entrez) gene: CFL2; cofilin 2

Disease synonyms

Related Diseases

Related human health report(s)

alcohol, response to, actin-mediated

alcohol, response to, RSU1-related

alcohol use disorder, susceptibility to (fly models overview)

Ortholog Information

Human gene(s) in FlyBase

Human gene (HGNC)

Symbol / Name

CFL2; cofilin 2

D. melanogaster ortholog (based on DIOPT)

Dmel\tsr

(DIOPT, 2013-)

Comments on ortholog(s)

Many to one: 2 human genes to 1 Drosophila gene.

Human gene (HGNC)

Symbol / Name

RAC1; Rac family small GTPase 1

D. melanogaster ortholog (based on DIOPT)

Dmel\Rac1

(DIOPT, 2013-)

Comments on ortholog(s)

Many to one: 2 human genes to 1 Drosophila gene.

Human gene (HGNC)

Symbol / Name

RAC2; Rac family small GTPase 2

D. melanogaster ortholog (based on DIOPT)

Dmel\Rac1

(DIOPT, 2013-)

Comments on ortholog(s)

Many to one: 2 human genes to 1 Drosophila gene.

Human gene (HGNC)

Symbol / Name

DSTN; destrin, actin depolymerizing factor

D. melanogaster ortholog (based on DIOPT)

Dmel\tsr

(DIOPT, 2013-)

Comments on ortholog(s)

Many to one: 2 human genes to 1 Drosophila gene.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (2)

Dmel\tsr

Gene Snapshot

Contributions welcome

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

Single, high-scoring ortholog of human genes Hsap\DSTN and CFL2.

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\Rac1

Gene Snapshot

Rac1 (Rac1) encodes a GTPase signaling protein that acts as a molecular switch, regulating cell shape, movement, division, and wound healing. It responds to signals from RTK and PIP3 pathways, activating the WAVE regulatory complex. This promotes the formation of branched actin filaments, helping cells move and change shape. [Date last reviewed: 2024-07-18]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

RHO
PVR-C

Comments on ortholog(s)

Single, high-scoring ortholog of human genes Hsap\RAC1 and Hsap\RAC2.

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 (36 groups)

tsr

protein-protein

Interacting group

Assay

References

tsr - CG7737

experimental knowledge based

(Guruharsha et al., 2011)

tsr - flr

anti tag coimmunoprecipitation, western blot

(Chu et al., 2012)

tsr - HIP-R

experimental knowledge based

(Guruharsha et al., 2011)

tsr - mbt

enzymatic study, autoradiography

(Menzel et al., 2007)

tsr - Nlg2

anti tag coimmunoprecipitation, western blot, Identification by mass spectrometry, pull down

(Sun et al., 2023)

tsr - Rack1

anti tag coimmunoprecipitation, western blot

(Sun et al., 2023)

tsr - scrib

anti tag coimmunoprecipitation, western blot

(Cervantes-Sandoval et al., 2016)

tsr - Sumo

anti tag coimmunoprecipitation, comigration in sds page, anti tag western blot

(Pirone et al., 2017)

tsr - Synd

experimental knowledge based

(Guruharsha et al., 2011)

tsr - Tango2

experimental knowledge based

(Guruharsha et al., 2011)

tsr - tobi

experimental knowledge based

(Guruharsha et al., 2011)

tsr - yki

bimolecular fluorescence complementation, fluorescence microscopy, anti tag coimmunoprecipitation, western blot, proximity ligation assay

(Skouloudaki et al., 2019)

Rac1

RNA-protein

Interacting group

Assay

References

Rac1 - Fmr1

anti bait coimmunoprecipitation, reverse transcription pcr

(Lee et al., 2003)

protein-protein

Interacting group

Assay

References

Rac1 - Arfip

anti tag coimmunoprecipitation, anti tag western blot, western blot

(Peru Y Colón de Portugal et al., 2012)

Rac1 - Atg8a

anti tag coimmunoprecipitation, western blot

(Tzou et al., 2025)

Rac1 - Cyfip

anti bait coimmunoprecipitation, western blot

(Schenck et al., 2003)

Rac1 - cyri

bimolecular fluorescence complementation, fluorescence microscopy, pull down, anti tag western blot

(Rötte et al., 2024)

Rac1 - Fhos

pull down, anti tag western blot

(Lammel et al., 2014)

Rac1 - Frl

pull down, autoradiography

(Dollar et al., 2016)

Rac1 - GEFmeso

enzymatic study

(Sundaram, 2015)

Rac1 - ics

anti tag coimmunoprecipitation, anti tag western blot

(Ojelade et al., 2015)

Rac1 - mbt

pull down, anti tag western blot

(Rötte et al., 2024)

Rac1 - Pak

pull down, autoradiography, western blot, anti tag western blot, two hybrid

(Nahm et al., 2006, Emoto et al., 2004, Fan et al., 2003, Hornstein et al., 2003, Hu et al., 2001, Newsome et al., 2000, Harden et al., 1996)

Rac1 - Pak3

anti tag coimmunoprecipitation, anti tag western blot, western blot

(Duan et al., 2012, Mentzel and Raabe, 2005)

Rac1 - pbl

enzymatic study, autoradiography

(van Impel et al., 2009)

Rac1 - Pkn

pull down, anti tag western blot, western blot

(Betson and Settleman, 2007, Lu and Settleman, 1999)

Rac1 - PlexB

pull down, autoradiography

(Driessens et al., 2001, Hu et al., 2001)

Rac1 - Rack1

anti tag coimmunoprecipitation, anti tag western blot

(Sun et al., 2023)

Rac1 - RhoGAP18B

anti tag coimmunoprecipitation, anti tag western blot

(Ojelade et al., 2015)

Rac1 - RhoGAP100F

pull down, anti tag western blot, enzymatic study, fluorescence technology

(Spinner et al., 2018)

Rac1 - RhoGEF3

pull down, autoradiography

(Nakamura et al., 2017)

Rac1 - scrib

anti tag coimmunoprecipitation, western blot

(Cervantes-Sandoval et al., 2016)

Rac1 - slpr

pull down, autoradiography, anti tag coimmunoprecipitation, western blot

(Garlena et al., 2010, Neisch et al., 2010)

Rac1 - trc

anti bait coimmunoprecipitation, anti tag western blot

(Emoto et al., 2004)

Rac1 - trio

enzymatic study, autoradiography

(van Impel et al., 2009, Newsome et al., 2000)

Rac1 - Whamy

pull down, anti tag western blot

(Brinkmann et al., 2016)

Alleles Reported to Model Human Disease (Disease Ontology) (20 alleles)

tsr

Models Based on Experimental Evidence ( 7 )

Allele

Disease

Evidence

References

tsr^HMS00534

model of nemaline myopathy 7

CEC

(Christophers et al., 2024)

CEA

(Balakrishnan et al., 2020)

tsr^N121

model of alcohol use disorder

CEA with RhoGAP18B¹

(Ojelade et al., 2015)

tsr^N96A

model of nemaline myopathy 7

CEA

(Balakrishnan et al., 2020)

model of autism spectrum disorder

CEA

(Sun et al., 2023)

tsr^S3A.UAS

model of alcohol use disorder

CEA

(Ojelade et al., 2015)

tsr^k05633

model of alcohol use disorder

CEA with RhoGAP18B¹

(Ojelade et al., 2015)

tsr^KK108706

model of nemaline myopathy 7

CEA

(Balakrishnan et al., 2020)

tsr^{V7M.UAS.Tag:HA}

model of nemaline myopathy 7

CEA

(Balakrishnan et al., 2020)

Modifiers Based on Experimental Evidence ( 7 )

Allele

Disease

Interaction

References

tsr^HMS00534

model of nemaline myopathy 7

is ameliorated by PI31^UAS.Tag:HA

(Balakrishnan et al., 2020)

is exacerbated by Prosβ6^1.B.UAS

(Balakrishnan et al., 2020)

tsr^N121

ameliorates hereditary systemic amyloidosis 1

modeled by Hsap\TTR^{V30M.UAS.Tag:HA}

(Oliveira da Silva et al., 2020)

exacerbates Huntington's disease

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

(Onur et al., 2021)

tsr^S3A.UAS

ameliorates Parkinson's disease 1

modeled by Hsap\SNCA^QUAS.cOa

(Sarkar et al., 2021)

tsr^{UAS.Tag:polyHis}

ameliorates tauopathy

modeled by Hsap\MAPT^V337M.UAS

(Fulga et al., 2007)

ameliorates Parkinson's disease 8

modeled by Lrrk^e03680

(Sarkar et al., 2021)

tsr^UAS.cNa

ameliorates Parkinson's disease 1

modeled by Hsap\SNCA^QUAS.cOa

(Sarkar et al., 2021)

tsr^UAS.EGFP

ameliorates autism spectrum disorder

modeled by Nlg2^KO70

(Sun et al., 2023)

tsr^S3A.UAS.EGFP

ameliorates autism spectrum disorder

modeled by Nlg2^KO70

(Sun et al., 2023)

Rac1

Models Based on Experimental Evidence ( 3 )

Allele

Disease

Evidence

References

Rac1^JF02813

model of kidney disease

CEA

(Zhang et al., 2013)

Rac1^DN.UAS.cUa

model of alcohol use disorder

CEA

(Rothenfluh et al., 2006)

Rac1^Y64D.UAS

model of autosomal dominant intellectual developmental disorder 48

CEC

(Banka et al., 2022)

Modifiers Based on Experimental Evidence ( 9 )

Allele

Disease

Interaction

References

Rac1^J11

ameliorates hereditary systemic amyloidosis 1

modeled by Hsap\TTR^{V30M.UAS.Tag:HA}

(Oliveira da Silva et al., 2020)

Rac1^UAS.cLa

ameliorates Machado-Joseph disease

modeled by Hsap\ATXN3^{tr.Q78.UAS.Tag:HA}

(Lee et al., 2011)

Rac1^V12.UAS

exacerbates Machado-Joseph disease

modeled by Hsap\ATXN3^{tr.Q78.UAS.Tag:HA}

(Lee et al., 2011)

ameliorates autism spectrum disorder

modeled by Fmr1^5-HA-1014

(Dong et al., 2016)

ameliorates Machado-Joseph disease

modeled by Hsap\ATXN3^{fl.Q84.UAS.Tag:MYC}

(Vu et al., 2018)

ameliorates Huntington's disease

modeled by Hsap\HTT^128Q.FL.UAS

(Vu et al., 2018)

Rac1^JF02813

exacerbates Alzheimer's disease 1

modeled by Hsap\APP^{Aβ42.UAS.Tag:SS(rPENK)}

(Kikuchi et al., 2020)

ameliorates neurodegenerative disease

modeled by ifc^KO

(Tzou et al., 2021)

Rac1^DN.UAS.cUa

ameliorates Alzheimer's disease 1

modeled by Hsap\APP^{Aβ42.UAS.cUa}

(Cheng et al., 2021)

Rac1^HMS01258

exacerbates Alzheimer's disease 1

modeled by Hsap\APP^{Aβ42.UAS.Tag:SS(rPENK)}

(Kikuchi et al., 2020)

Rac1^GD17411

exacerbates Huntington's disease

modeled by Hsap\HTT^{Q91.ex1.QUAS.mCherry}

(Pearce et al., 2015)

Rac1^UAS.cUa

ameliorates Machado-Joseph disease

modeled by Hsap\ATXN3^{tr.Q78.UAS.Tag:HA}

(Chung et al., 2017)

Rac1^Y64D.UAS

model of autosomal dominant intellectual developmental disorder 48

is ameliorated by Cyfip^HMS01754

(Banka et al., 2022)

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\RAC1^{PA.Q61L.UAS.Tag:AsLOV2}

P{UAS-PA-RacQ61L}

Hsap\RAC1^{PA.T17N.UAS.Tag:AsLOV2}

P{UAS-PA-RacT17N}

Hsap\RAC1^{C450M.PA.Q61L.UAS}

P{UAS-C450M-PA-RacQ61L}

Hsap\RAC1^{C450M.PA.T17N.UAS}

P{UAS-C450M-PA-RacT17N}

Hsap\RAC1^Rac-FRET.UAS

P{UAS-YPet-PAK-RAC-CFP.FRET}

w^*; sna^Sco/CyO; P{UAS-YPet-PAK-RAC-CFP.FRET}3

Hsap\RAC1^{PA.Q61L.UAS.mCherry,Tag:AsLOV2}

P{UAS-mCherry-PA-RacQ61L}

w^*; sna^Sco/CyO; P{UAS-mCherry-PA-RacQ61L}3/TM6B, Tb¹

Hsap\RAC1^{PA.T17N.UAS.mCherry,Tag:AsLOV2}

P{UAS-mCherry-PA-RacT17N}

w^*; P{UAS-mCherry-PA-RacT17N}2; MKRS/TM6B, Tb¹

Hsap\RAC1^{C450M.PA.Q61L.UAS.mCherry}

P{UAS-mCherry-C450M-PA-RacQ61L}

w^*; sna^Sco/CyO; P{UAS-mCherry-C450M-PA-RacQ61L}3

Hsap\RAC2^UAS.Tag:HA

M{UAS-hRAC2.HA}

y¹ w^*; M{UAS-hRAC2.HA}ZH-86Fb

Hsap\DSTN^{UAS.cBa.Tag:HA}

PBac{UAS-hDSTN.HA}

y¹ w^*; PBac{UAS-hDSTN.HA}VK00033

Hsap\DSTN^UAS.Tag:HA

M{UAS-hDSTN.HA}

y¹ w^*; M{UAS-hDSTN.HA}ZH-86Fb

Selected Drosophila transgenes

Allele

Transgene

Publicly Available Stocks

PBac{UAS-tsr.S3A.EGFP}

tsr^UAS.cNa

P{UAS-tsr.N}

P{UAS-tsr.N}1.7, y¹ w^*; βTub60D^Pin-1/CyO

tsr^S3A.UAS

P{UAS-tsr.S3A}

P{UAS-tsr.S3A}4.1, y¹ w^*; βTub60D^Pin-1/CyO

tsr^{UAS.Tag:polyHis}

y¹ w^*; P{UAS-Rac1.L}3

Rac1^V12.UAS

P{UAS-Rac1.V12}

y¹ w^*; P{UAS-Rac1.V12}1

Rac1^DN.UAS.cUa

P{UAS-Rac1.DN.U}

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

y¹ sc^* v¹ sev²¹; P{TRiP.HMS00534}attP2

w¹¹¹⁸; P{GD17411}v49246

y¹ v¹; P{TRiP.JF02813}attP2 e^*

Rac1^HMS01258

P{TRiP.HMS01258}

y¹ sc^* v¹ sev²¹; P{TRiP.HMS01258}attP2

Rac1^NIG.2248R

P{NIG.2248R}

P{NIG.2248R}1

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

tsr^k05633

P-element activity

y¹ w^67c23; P{lacW}tsr^k05633/CyO

tsr^N121

loss of function allele

P-element activity

w^*; P{FRT(w^hs)}G13 tsr^N121/CyO

tsr^N96A

loss of function allele

P-element activity

y¹ w^*; P{FRT(w^hs)}G13 tsr^N96A/CyO

tsr^Δ96

loss of function allele

Rac1^J11

loss of function allele

ethyl methanesulfonate

y¹ w^*; Rac1^J11 Rac2^Δ P{FRT(w^hs)}2A/TM6B, Tb⁺

Rac1^J10

loss of function allele

ethyl methanesulfonate

y¹ w^*; Rac1^J10 Rac2^Δ P{FRT(w^hs)}2A Mtl^Δ/TM6B, Tb¹

Rac1^J6

loss of function allele

ethyl methanesulfonate

References (3)

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