FlyBase Allele Report: Dmel\Ret[MEN2B.UAS]

General Information

Symbol

Dmel\Ret^MEN2B.UAS

Species

D. melanogaster

Name

FlyBase ID

FBal0352210

Feature type

allele

Associated gene

Dmel\Ret

Associated Insertion(s)

Carried in Construct

P{UAS-Ret.MEN2B}

Also Known As

dRet^MEN2B, Ret^MEN2B, UAS-Ret^MEN2B

Key Links

Genomic Maps

JBrowse

Transgenic product class

missense_variant

(Das and Cagan, 2017)

Mutagen

in vitro construct

Nature of the Allele

Transgenic product class

missense_variant

(Das and Cagan, 2017)

Mutagen

in vitro construct

(Das and Cagan, 2017, Das et al., 2013)

Progenitor genotype

Ret^MEN2B.GMR

(Das et al., 2013)

Carried in construct

P{UAS-Ret.MEN2B}

Cytology

Description

UAS regulates expression of Ret containing an activating point mutation (M955T), orthologous to a Hsap\RET variant commonly observed in medullary thyroid carcinoma patients.

(Das and Cagan, 2017)

The GMR regulatory sequences in Ret^MEN2B.GMR have been replaced by UASt.

(Das et al., 2013)

Allele components

Component

Use(s)

Regulatory region(s)

UAS

binary expression system - regulatory region

UASt

binary expression system - regulatory region

Encoded product / tool

Ret

Mutations Mapped to the Genome

Curation Data

Type

Location

Additional Notes

References

point_mutation

2L:21,184,017..21,184,017 [-]

Comment:

Analogous mutation in human RET implicated in multiple endocrine neoplasia, type IIA; mutation carried on in vitro construct; site of nucleotide substitution in fly gene inferred by FlyBase curator based on reported amino acid change.

(Das et al., 2013)

Variant Molecular Consequences

Associated Sequence Data

DDBJ / EMBL / GenBank

DNA sequence

Protein sequence

UniProtKB/Swiss-Prot

UniProtKB/TrEMBL

Expression Data

Reporter Expression

Additional Information

Statement

Reference

Marker for

Reflects expression of

Reporter construct used in assay

Human Disease Associations

Disease Ontology (DO) Annotations

Models Based on Experimental Evidence ( 1 )

Disease

Evidence

References

model of cancer

CEA

(Das et al., 2013, Dar et al., 2012)

CEA with Nek2^UAS.GFP

(Das et al., 2013)

model of multiple endocrine neoplasia type 2B

CEA

(Fereres et al., 2019, Sonoshita et al., 2018)

Modifiers Based on Experimental Evidence ( 1 )

Disease

Interaction

References

DOES NOT ameliorate Parkinson's disease

modeled by Pink1^B9

(Klein et al., 2014)

ameliorates Parkinson's disease

modeled by Pink1^B9

(Klein et al., 2014)

model of multiple endocrine neoplasia type 2B

is exacerbated by Lk6²

(Sonoshita et al., 2018)

is ameliorated by Lk6^RNAi.UAS.cUa

(Sonoshita et al., 2018)

is ameliorated by Raf⁷

(Sonoshita et al., 2018)

is ameliorated by Irk2^DN.UAS

(Fereres et al., 2019)

is ameliorated by SCAR^GD11380

(Fereres et al., 2019)

is ameliorated by dia^GL00408

(Fereres et al., 2019)

Comments on Models/Modifiers Based on Experimental Evidence ( 0 )

Disease-implicated variant(s)

This allele represents a human variant implicated in disease.

(Das and Cagan, 2017)

RET:p.Met918Thr

(FlyBase curators, 2019-)

Variants Synonym(s)

RET:p.Met664Thr

Associated human disease model(s)

External database links

ClinVar: RET_13919

Comments concerning this variant

Phenotypic Data

Phenotypic Class

abnormal size, with Scer\GAL4^ptc-559.1

(Das et al., 2013)

increased cell number | larval stage, with Scer\GAL4^ptc-559.1

(Fereres et al., 2019)

lethal, with Scer\GAL4^Mhc.PK

(Klein et al., 2014)

lethal | heat sensitive, with Scer\GAL4^Mef2.PR

(Klein et al., 2014)

lethal - all die before end of P-stage, with Scer\GAL4^ptc-559.1

(Fereres et al., 2019)

lethal - all die before end of pupal stage, with Scer\GAL4^ptc-559.1

(Dar et al., 2012)

some die during P-stage, with Scer\GAL4^ptc-559.1

(Fereres et al., 2019)

viable, with Scer\GAL4^C-765

(Dar et al., 2012)

visible, with Scer\GAL4^C-765

(Dar et al., 2012)

visible | adult stage, with Scer\GAL4^C-765

(Das and Cagan, 2017)

visible | adult stage | somatic clone

(Das et al., 2013)

Phenotype Manifest In

anterior-posterior compartment boundary of the wing disc, with Scer\GAL4^ptc-559.1

(Fereres et al., 2019)

eye | somatic clone

(Das et al., 2013)

indirect flight muscle cell, with Scer\GAL4^Mef2.PR

(Klein et al., 2014)

mesonotum, with Scer\GAL4^ptc-559.1

(Dar et al., 2012)

scutellum | pupal stage, with Scer\GAL4^ptc-559.1

(Dar et al., 2012)

wing, with Scer\GAL4^C-765

(Dar et al., 2012)

wing disc, with Scer\GAL4^ptc-559.1

(Das et al., 2013)

wing vein | ectopic, with Scer\GAL4^C-765

(Das and Cagan, 2017, Dar et al., 2012)

Detailed Description

Statement

Reference

Expressing Ret^MEN2B.UAS in the wing disc ptc domain, using Scer\GAL4^ptc-559.1 as a driver, leads to an expansion of the ptc domain.

(Fereres et al., 2019)

Expressing Ret^M955T.UAS under the control of Scer\GAL4^C-765, but not Scer\GAL4^ptc.PU, leads to adult wings with ectopic veins.

(Das and Cagan, 2017)

Expression of Ret^{MEN2B.Scer\UAS} under the control of Scer\GAL4^Mef2.PR causes lethality at 25[o]C, but at 18[o]C viable progeny eclose with lower frequency. Surviving transgenic flies display an "actin blob" phenotype. Mild indirect flight muscle abnormalities are seen, including deposits of actin dispersed over the muscle tissues, and some abnormally thick and irregular myofibrils. Mitochondrial morphology is normal. Thoracic ATP levels are slightly reduced compared to controls.

Flies overexpressing Ret^{MEN2B.Scer\UAS} under the control of Scer\GAL4^Mhc.PK (limited to the pharate adult stages onwards using Scer\GAL80^ts.αTub84B) do not exhibit any indirect flight muscle phenotypes.

Expression of Ret^{MEN2B.Scer\UAS} in dopaminergic neurons under the control of Scer\GAL4^ple.PF has no effect on mitochondrial morphology.

(Klein et al., 2014)

Expression of Ret^{MEN2B.Scer\UAS} under the control of Scer\GAL4^ptc-559.1 results in mild overgrowth in the developing wing epithelium and minimal migration of cells from the ptc domain compared to controls.

(Das et al., 2013)

Expression of Ret^{MEN2B.Scer\UAS} under the control of Scer\GAL4^ptc-559.1 has very little effect on migration in the wing disc, with very few cells migrating away from the A-P boundary. There is very little effect on the cytoskeletal tubulin network.

Eye clones expressing Ret^{MEN2B.Scer\UAS} (generated using the ey-FLP system) have very rough eyes that retain their pigmentation.

(Das et al., 2013)

Flies expressing Ret^{MEN2B.Scer\UAS} under the control of Scer\GAL4^ptc-559.1 are lethal; no adults are obtained and 50% of animals make it to the pupal stage. Notum and scuttellum phenotypes are seen in the un-eclosed pupae.

Expression of Ret^{MEN2B.Scer\UAS} under the control of Scer\GAL4^ptc-559.1 also causes larval wing disc phenotypes including overproliferation, basal constriction and cell migration away from the ptc domain.

Expression of Ret^{MEN2B.Scer\UAS} under the control of Scer\GAL4^C-765 leads to disruption of the overall wing pattern, including ectopic wing veins.

The lethality seen in flies expressing Ret^{MEN2B.Scer\UAS} under the control of Scer\GAL4^ptc-559.1 is significantly suppressed by oral administration of clinical kinase inhibitors. Vandetanib produces weak rescue, sunitinib mild rescue and sorafenib stronger rescue. Although sorafenib rescues some animals to adulthood, it does not considerably increase the proportion that develop to pupariation. The lethality associated with flies expressing Ret^{MEN2B.Scer\UAS} under the control of Scer\GAL4^ptc-559.1 is also suppressed by the compound AD57, with 25% of those that are rescued to adulthood fully active and fertile. However both AD57 and Sorafenib result in adults that exhibit some cuticle defects. The notum and scuttellum phenotypes seen in the un-eclosed pupae are also rescued by AD57. The wing disc overproliferation, basal constriction and migration are also rescued by AD57, as well as by sorafenib, sunitinib and vandetanib, but more weakly. AZD-6244 has no effect on viability.

The wing patterning and ectopic wing vein phenotypes seen when Ret^{MEN2B.Scer\UAS} is expressed under the control of Scer\GAL4^C-765 are suppressed by the compound AD57, but Vandetanib has little effect. AD58 slightly but consistently enhances the phenotype. Combining AD58 and Sorafenib considerably suppresses invasion and migration in the wing discs, even though no effect is seen with either compound alone. AD36 results in increased invasion but this does not result in an increase in lethality. Migration is blocked upon co-treatment with AD58 and sorafenib, but not with either compound alone.

Oral administration of either AD80 or AD81 to flies expressing Ret^{MEN2B.Scer\UAS} under the control of Scer\GAL4^ptc-559.1 significantly suppresses the lethality, with 70-90% of animals developing to adulthood. The resulting adult flies appear phenotypically normal.

(Dar et al., 2012)

External Data

Linkouts

Interactions

Show genetic interaction network for Enhancers & Suppressors

Phenotypic Class

Enhanced by

Statement

Reference

Ret^MEN2B.UAS, Scer\GAL4^ptc-559.1 has abnormal size phenotype, enhanceable by Sin3A^KK100700, Scer\GAL4^ptc-559.1

(Das et al., 2013)

Ret^MEN2B.UAS has visible | adult stage | somatic clone phenotype, enhanceable by Nek2^UAS.GFP

(Das et al., 2013)

Suppressed by

Statement

Reference

Ret^MEN2B.UAS, Scer\GAL4^ptc-559.1 has increased cell number | larval stage phenotype, suppressible by Irk2^DN.UAS, Scer\GAL4^ptc-559.1

(Fereres et al., 2019)

Ret^MEN2B.UAS, Scer\GAL4^ptc-559.1 has increased cell number | larval stage phenotype, suppressible by dia^HM05027, Scer\GAL4^ptc-559.1

(Fereres et al., 2019)

Ret^MEN2B.UAS, Scer\GAL4^ptc-559.1 has increased cell number | larval stage phenotype, suppressible by SCAR^GD11380, Scer\GAL4^ptc-559.1

(Fereres et al., 2019)

Ret^MEN2B.UAS has increased mortality during development phenotype, suppressible by Scer\GAL4^ptc-559.1/Irk2^DN.UAS

(Fereres et al., 2019)

Ret^MEN2B.UAS has partially lethal - majority die phenotype, suppressible by Scer\GAL4^ptc-559.1/Irk2^DN.UAS

(Fereres et al., 2019)

Ret^MEN2B.UAS has increased mortality during development phenotype, suppressible by Scer\GAL4^ptc-559.1/dia^HM05027

(Fereres et al., 2019)

Ret^MEN2B.UAS has partially lethal - majority die phenotype, suppressible by Scer\GAL4^ptc-559.1/dia^HM05027

(Fereres et al., 2019)

Ret^MEN2B.UAS has increased mortality during development phenotype, suppressible by Scer\GAL4^ptc-559.1/SCAR^GD11380

(Fereres et al., 2019)

Ret^MEN2B.UAS has partially lethal - majority die phenotype, suppressible by Scer\GAL4^ptc-559.1/SCAR^GD11380

(Fereres et al., 2019)

Other

Statement

Reference

Nek2^UAS.GFP, Ret^MEN2B.UAS, Scer\GAL4^ptc-559.1 has abnormal cell migration phenotype

(Das et al., 2013)

Phenotype Manifest In

Enhanced by

Statement

Reference

Ret^MEN2B.UAS, Scer\GAL4^ptc-559.1 has wing disc phenotype, enhanceable by Sin3A^KK100700, Scer\GAL4^ptc-559.1

(Das et al., 2013)

Ret^MEN2B.UAS has eye | somatic clone phenotype, enhanceable by Nek2^UAS.GFP

(Das et al., 2013)

Suppressed by

Statement

Reference

Ret^MEN2B.UAS, Scer\GAL4^ptc-559.1 has anterior-posterior compartment boundary of the wing disc phenotype, suppressible by Irk2^DN.UAS, Scer\GAL4^ptc-559.1

(Fereres et al., 2019)

Ret^MEN2B.UAS, Scer\GAL4^ptc-559.1 has anterior-posterior compartment boundary of the wing disc phenotype, suppressible by dia^HM05027, Scer\GAL4^ptc-559.1

(Fereres et al., 2019)

Ret^MEN2B.UAS, Scer\GAL4^ptc-559.1 has anterior-posterior compartment boundary of the wing disc phenotype, suppressible by SCAR^GD11380, Scer\GAL4^ptc-559.1

(Fereres et al., 2019)

Ret^MEN2B.UAS, Scer\GAL4^Mef2.PR has indirect flight muscle cell phenotype, suppressible | partially by Pink1^B9

(Klein et al., 2014)

Ret^MEN2B.UAS, Scer\GAL4^Mef2.PR has indirect flight muscle cell phenotype, suppressible | partially by park¹/park²⁵

(Klein et al., 2014)

Suppressor of

Statement

Reference

Ret^MEN2B.UAS/Scer\GAL4^Mef2.PR is a suppressor | partially of indirect flight muscle cell phenotype of Pink1^B9

(Klein et al., 2014)

Ret^MEN2B.UAS/Scer\GAL4^Mef2.PR is a suppressor | partially of dopaminergic neuron phenotype of Pink1^B9

(Klein et al., 2014)

Ret^MEN2B.UAS, Scer\GAL4^Mef2.PR, Scer\GAL80^ts.αTub84B is a suppressor | partially of indirect flight muscle cell phenotype of Pink1^B9

(Klein et al., 2014)

Ret^MEN2B.UAS/Scer\GAL4^Mef2.PR is a suppressor | partially of mitochondrion phenotype of Pink1^B9

(Klein et al., 2014)

NOT Suppressor of

Statement

Reference

Ret^MEN2B.UAS/Scer\GAL4^Mef2.PR is a non-suppressor of indirect flight muscle cell phenotype of park¹/park²⁵

(Klein et al., 2014)

Scer\GAL4^Mhc.PK, Ret^MEN2B.UAS, Scer\GAL80^ts.αTub84B is a non-suppressor of indirect flight muscle cell phenotype of park¹/park²⁵

(Klein et al., 2014)

Ret^MEN2B.UAS/Scer\GAL4^Mef2.PR is a non-suppressor of mitochondrion phenotype of park¹/park²⁵

(Klein et al., 2014)

Ret^MEN2B.UAS/Scer\GAL4^Mef2.PR is a non-suppressor of dopaminergic neuron phenotype of park¹/park²⁵

(Klein et al., 2014)

Other

Statement

Reference

Ret^MEN2B.UAS, Scer\GAL4^ptc-559.1, dia^HM05027 has wing vein phenotype

(Fereres et al., 2019)

Nek2^UAS.GFP, Ret^MEN2B.UAS, Scer\GAL4^ptc-559.1 has wing disc phenotype

(Das et al., 2013)

Nek2^UAS.GFP, Ret^MEN2B.UAS has proboscis | somatic clone phenotype

(Das et al., 2013)

Additional Comments

Genetic Interactions

Statement

Reference

The surviving adults that co-express Ret^MEN2B.UAS and dia^HM05027 under the control of Scer\GAL4^ptc-559.1 have normal morphology, and with the exception of small wing vein abnormalities, the wings are indistinguishable from wild-type controls.

(Fereres et al., 2019)

Expression of Ret^{MEN2B.Scer\UAS} under the control of Scer\GAL4^Mef2.PR partially suppresses the muscle morphology phenotype seen in the indirect flight muscles of Pink1^B9 mutants. The frequency of flies with "actin blobs" is also decreased markedly compared to Ret^{MEN2B.Scer\UAS} expressing controls. The fraction of severely impaired mitochondria is decreased and the fraction of mitochondria with wild type-like cristae is increased. The reduction in thoracic ATP levels is largely rescued, as is the reduction in Complex 1 activity.

Expression of Ret^{MEN2B.Scer\UAS} under the control of Scer\GAL4^Mef2.PR does not suppress the muscle morphology phenotype seen in the indirect flight muscles of park¹/park²⁵ mutants. The frequency of flies with "actin blobs" is decreased markedly compared to Ret^{MEN2B.Scer\UAS} expressing controls. The structural impairments seen in park¹/park²⁵ mutant mitochondria are not suppressed. The reduction in thoracic ATP levels is not rescued.

Expression of Ret^{MEN2B.Scer\UAS} under the control of Scer\GAL4^Mhc.PK (limited to the pharate adult stages onwards using Scer\GAL80^ts.αTub84B) largely suppresses the muscle morphology phenotype seen in the indirect flight muscles of Pink1^B9 mutants.

Expression of Ret^{MEN2B.Scer\UAS} under the control of Scer\GAL4^Mhc.PK (limited to the pharate adult stages onwards using Scer\GAL80^ts.αTub84B) does not suppress the muscle morphology phenotype seen in the indirect flight muscles of park¹/park²⁵ mutants.

Expression of Ret^{MEN2B.Scer\UAS} under the control of Scer\GAL4^ple.PF suppresses the mitochondrial morphology defects seen in Pink1^B9 mutant dopaminergic neurons.

Expression of Ret^{MEN2B.Scer\UAS} under the control of Scer\GAL4^ple.PF does not suppress the mitochondrial morphology defects seen in park¹/park²⁵ mutant dopaminergic neurons.

Expression of Ret^{MEN2B.Scer\UAS} does not suppress the reduction in Complex I activity seen when CG11455^GD4800 is expressed under the control of Scer\GAL4^Mef2.PR.

(Klein et al., 2014)

Expression of Sin3A^KK100700 enhances the wing disc phenotypes seen when Ret^{MEN2B.Scer\UAS} is expressed under the control of Scer\GAL4^ptc-559.1. Large numbers of cells are shifted basally below the epithelium and migrate significant distances from the ptc domain.

(Das et al., 2013)

Co-expression of Ret^{MEN2B.Scer\UAS} and Nek2^{Scer\UAS.T:Avic\GFP} under the control of Scer\GAL4^ptc-559.1 results in a large number of cells migrating away from the A-P boundary into the adjacent compartment. Extensive rearrangement of the cytoskeletal tubulin network is also seen.

Expression of Nek2^{Scer\UAS.T:Avic\GFP} enhances the rough eye phenotype seen in eye clones expressing Ret^{MEN2B.Scer\UAS}, emergence of unpigmented, undifferentiated cells in the adult eye and the presence of clonal cells in tissues adjacent to the eye, including the proboscis.

Expression of Ret^{MEN2B.Scer\UAS} enhances the "distant seeding" phenotype seen when Nek2^{Scer\UAS.T:Avic\GFP} is expressed under the control of Scer\GAL4^GMR.PF. Larger groups of Avic\GFP-positive cells are detected in distant body parts. This phenotype is significantly reduced when flies also carry one copy each of Pi3K21B^unspecified and S6k^unspecified. The phenotype can also be suppressed by drugs that inhibit signalling along the PI3K cascade; LY294002, Rapamycin, MK2206 or BEZ235.

(Das et al., 2013)

One copy of rl¹ suppresses the enhanced lethality seen when flies expressing Ret^{MEN2B.Scer\UAS} under the control of Scer\GAL4^ptc-559.1 are treated with AD58.

One copy of rl¹ further suppresses the rescuing effect of AD57 on the lethality of flies expressing Ret^{MEN2B.Scer\UAS} under the control of Scer\GAL4^ptc-559.1.

One copy of rl¹ has no effect on the viability of flies expressing Ret^{MEN2B.Scer\UAS} under the control of Scer\GAL4^ptc-559.1 treated with AZD-6244.

One copy of Tor^unspecified suppresses the rescuing effect of AD57 on the lethality of flies expressing Ret^{MEN2B.Scer\UAS} under the control of Scer\GAL4^ptc-559.1, resulting in an increased frequency of lethality than in the absence of the drug.

One copy of Tor^unspecified further enhances the increased lethality seen when flies expressing Ret^{MEN2B.Scer\UAS} under the control of Scer\GAL4^ptc-559.1 are fed AD58.

One copy of S6k^unspecified suppresses the lethality seen when flies expressing Ret^{MEN2B.Scer\UAS} under the control of Scer\GAL4^ptc-559.1 are fed AD58.

One copy of rl¹ suppresses the wing pattern and ectopic wing vein phenotypes seen when Ret^{MEN2B.Scer\UAS} is expressed under the control of Scer\GAL4^C-765.

One copy of rl¹ further suppresses the enhanced wing pattern and ectopic wing vein phenotypes seen when flies expressing Ret^{MEN2B.Scer\UAS} is expressed under the control of Scer\GAL4^C-765 are treated with AD58.

One copy of rl¹ suppresses the rescuing effect of AD57 on the wing pattern and ectopic wing vein phenotypes seen when Ret^{MEN2B.Scer\UAS} under the control of Scer\GAL4^C-765.

AD58 enhances the wing phenotypes seen in flies expressing Ret^{MEN2B.Scer\UAS} under the control of Scer\GAL4^C-765 in a Tor^unspecified/+ background.

One copy of rl¹ has no effect on the rescuing effect of AD80 or AD81 on the lethality of flies expressing Ret^{MEN2B.Scer\UAS} under the control of Scer\GAL4^ptc-559.1.

One copy of Tor^unspecified increases proliferation in the larval wing discs of flies expressing Ret^{MEN2B.Scer\UAS} under the control of Scer\GAL4^ptc-559.1 that have been fed AD58.

(Dar et al., 2012)

Xenogenetic Interactions

Statement

Reference

Complementation and Rescue Data

Comments

Images (0)

Mutant

Wild-type

Stocks (0)

Notes on Origin

Discoverer

External Crossreferences and Linkouts ( 0 )

Synonyms and Secondary IDs (3)

Reported As

Symbol Synonym

Ret^M955T.UAS

Ret^{MEN2B.Scer\UAS}

Ret^MEN2B.UAS

Name Synonyms

Secondary FlyBase IDs

FBal0291680
FBal0346153

References (8)

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