Human Disease Model Report: intestinal dysfunction, RET-related

General Information

Name

intestinal dysfunction, RET-related

FlyBase ID

FBhh0000995

Disease Ontology Term

Hirschsprung's disease

Parent Disease

OMIM

Overview

The human RET gene is associated with intestinal dysfunction in a number of disease contexts. It is a major susceptibility locus for Hirschsprung disease, also known as congenital intestinal aganglionosis (MIM:142623, FBhh0000994). Intestinal dysfunction may be present in subtypes of multiple endocrine neoplasia (MEN2B, FBhh0000014; MEN2A, FBhh0000013) that are associated with RET. There is a single high-scoring fly ortholog of RET, Dmel\Ret, for which RNAi-targeting constructs, alleles caused by insertional mutagenesis, and amorphic alleles created by targeted recombination have been generated.

A UAS construct of the wild-type human Hsap\RET gene has been introduced into flies, but has not been characterized in the context of this disease. The human RET gene has also been introduced into flies as a component of cancer-implicated fusion genes (see FBhh0000660). The RET gene is implicated in multiple other diseases, including several types of cancer; see MIM:164761. For relevant human disease models in flies, see the Dmel\Ret gene report.

Experiments in Drosophila indicate that Dmel\Ret is expressed in both enteric neurons (recapitulating findings in other systems) and in adult intestinal epithelial progenitors (a new and unexpected result). Ret is required for development of the stomatogastric (enteric) nervous system in both embryos and larvae. Animals homozygous for amorphic alleles exhibit severe feeding defects and typically die during the larval stage. In adult animals, Ret is also expressed in intestinal epithelial progenitors, where it plays a role in sustaining their proliferative capacity. This raises the possibility that there may be an epithelial contribution to RET loss-of-function disorders such as Hirschsprung disease.

A small number of physical interactions and many genetic interactions have been described for Dmel\Ret; see below and in the Ret gene report.

[updated Apr. 2020 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: intestinal dysfunction, RET-related

OMIM report

Human gene(s) implicated

Symptoms and phenotype

Genetics

Susceptibility to Hirschsprung disease 1 (HSCR1) is associated with variation in the RET gene; familial forms exhibit autosomal dominant inheritance. Hirschsprung disease has been observed in association with MEN2A (Verdy et al., 1982; pubmed:6136579) and gastrointestinal symptoms are a significant component of MEN2B (Mahaffey et al., 1990; pubmed:1967641), both of which are caused by mutation in the RET gene. [from MIM:142623; 2019.03.25]

(OMIM, 2013-)

Cellular phenotype and pathology

Molecular information

External links

Gene2Function (human gene): RET
Gene Cards: RET
MedlinePlus (condition): Hirschsprung disease
MedlinePlus (gene): RET
MARRVEL (human gene): RET
NCBI MedGen: Hirschsprung disease 1 (HSCR1)
NCBI (Entrez) gene: RET; ret proto-oncogene
National Organization for Rare Disorders: Hirschsprung Disease

Disease synonyms

Related Diseases

Related human health report(s)

Hirschsprung disease, susceptibility to, 1

multiple endocrine neoplasia, type IIA

multiple endocrine neoplasia, type IIB

Ortholog Information

Human gene(s) in FlyBase

Hsap\RET

Human gene (HGNC)

Symbol / Name

RET; ret proto-oncogene

D. melanogaster ortholog (based on DIOPT)

Dmel\Ret

(DIOPT, 2013-)

Comments on ortholog(s)

One to one: 1 human to 1 Drosophila.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (1)

Dmel\Ret

Gene Snapshot

Ret oncogene (Ret) encodes a cell surface receptor mediating dendrite development of class IV dendritic arborization sensory neurons. It interacts with integrins and mediates rac1 signaling to promote dendrite adhesion to the extracellular matrix. [Date last reviewed: 2019-03-14]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

Moderate-scoring ortholog of human RET (1 Drosophila to 1 human). Dmel\Ret shares 30% identity and 43% 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

H. sapiens (Human)

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

Summary of Physical Interactions (2 groups)

Ret

protein-protein

Interacting group

Assay

References

Ret - Gfrl

pull down, western blot, molecular weight estimation by staining, anti bait coimmunoprecipitation, anti tag western blot

(Myers et al., 2018, Saarenpää et al., 2017)

Ret - mys

anti tag coimmunoprecipitation, anti tag western blot

(Soba et al., 2015)

Alleles Reported to Model Human Disease (Disease Ontology) (12 alleles)

Ret

Models Based on Experimental Evidence ( 9 )

Allele

Disease

Evidence

References

Ret^GMR.PR

model of familial medullary thyroid carcinoma

CEA

(Vidal et al., 2005)

Ret^MEN2A.GMR

model of multiple endocrine neoplasia type 2A

CEA

(Read et al., 2005)

CEC

(Macagno et al., 2014)

model of familial medullary thyroid carcinoma

CEA

(Vidal et al., 2005)

Ret^MEN2B.GMR

model of multiple endocrine neoplasia type 2B

CEA

(Read et al., 2005)

model of familial medullary thyroid carcinoma

CEA

(Vidal et al., 2005)

Ret^KK107206

model of Hirschsprung's disease

CEA

(Myers et al., 2018)

Ret^MEN2A.UAS

model of multiple endocrine neoplasia type 2A

CEC

(Macagno et al., 2014)

Ret^LM1

model of Hirschsprung's disease

CEA

(Myers et al., 2018)

Ret^LM2

model of Hirschsprung's disease

CEA

(Myers et al., 2018)

Ret^LM3

model of Hirschsprung's disease

CEA

(Myers et al., 2018)

Ret^MEN2B.UAS

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 ( 7 )

Allele

Disease

Interaction

References

Ret^MEN2A.GMR

model of multiple endocrine neoplasia type 2A

is exacerbated by Mi-2^S005504

(Read et al., 2005)

is ameliorated by kis^k10237

(Read et al., 2005)

is exacerbated by Sin3A^ex4

(Read et al., 2005)

is ameliorated by S^k09538a

(Read et al., 2005)

is exacerbated by msn^j1E2

(Read et al., 2005)

is ameliorated by S^IIN

(Read et al., 2005)

is exacerbated by Mi-2^S147412

(Read et al., 2005)

is ameliorated by spi¹

(Read et al., 2005)

is exacerbated by Sin3A⁰⁸²⁶⁹

(Read et al., 2005)

is ameliorated by Ras85D⁰⁶⁶⁷⁷

(Read et al., 2005)

is ameliorated by Delta^S049520

(Read et al., 2005)

is exacerbated by hh^rJ413

(Read et al., 2005)

is ameliorated by Delta^9P

(Read et al., 2005)

is ameliorated by ebi^k16213

(Read et al., 2005)

is ameliorated by spi^s3547

(Read et al., 2005)

is ameliorated by drk¹⁰⁶²⁶

(Read et al., 2005)

is exacerbated by hh²

(Read et al., 2005)

is ameliorated by Fak^UAS.Tag:HA

(Macagno et al., 2014)

Ret^MEN2B.GMR

model of multiple endocrine neoplasia type 2B

is exacerbated by Sin3A^HW52

(Read et al., 2005)

is ameliorated by drk^k02401

(Read et al., 2005)

is ameliorated by drk^k13809

(Read et al., 2005)

is ameliorated by kis^k13416

(Read et al., 2005)

is exacerbated by hh^rJ413

(Read et al., 2005)

is ameliorated by Delta^S049520

(Read et al., 2005)

is ameliorated by S^IIN

(Read et al., 2005)

is exacerbated by Sin3A⁰⁸²⁶⁹

(Read et al., 2005)

is ameliorated by spi⁰¹⁰⁶⁸

(Read et al., 2005)

is ameliorated by S^k09538a

(Read et al., 2005)

is exacerbated by msn⁰³³⁴⁹

(Read et al., 2005)

is exacerbated by Sin3A^k07401

(Read et al., 2005)

is exacerbated by Sin3A^k08919

(Read et al., 2005)

is ameliorated by S^k09530

(Read et al., 2005)

is exacerbated by hh²

(Read et al., 2005)

is ameliorated by hh^neo56

(Read et al., 2005)

is ameliorated by Delta^9P

(Read et al., 2005)

is exacerbated by Mi-2^S147412

(Read et al., 2005)

is ameliorated by ebi^k16213

(Read et al., 2005)

is exacerbated by Mi-2^j3D4

(Read et al., 2005)

is exacerbated by Mi-2^S047526

(Read et al., 2005)

is ameliorated by kis^k16510

(Read et al., 2005)

is ameliorated by drk¹⁰⁶²⁶

(Read et al., 2005)

is ameliorated by spi^s3547

(Read et al., 2005)

is exacerbated by Csk^j1D8

(Read et al., 2005)

is exacerbated by hh^AC

(Read et al., 2005)

is ameliorated by kis^k10237

(Read et al., 2005)

is ameliorated by spi¹

(Read et al., 2005)

is ameliorated by Ras85D⁰⁶⁶⁷⁷

(Read et al., 2005)

is exacerbated by Sin3A^ex4

(Read et al., 2005)

is ameliorated by Ras85D^ΔC40B

(Read et al., 2005)

is exacerbated by msn^j1E2

(Read et al., 2005)

is exacerbated by Mi-2^S005504

(Read et al., 2005)

model of cancer

is exacerbated by Sin3A^KK100700

(Das et al., 2013)

Ret^K805A.UAS

DOES NOT ameliorate neurofibromatosis

modeled by Nf1^E2

(Walker et al., 2013)

Ret^HMC03102

ameliorates lung adenocarcinoma

modeled by Hsap\KIF5B::Hsap\RET^UAS.cDa

(Das and Cagan, 2017)

Ret^MEN2A.UAS

model of multiple endocrine neoplasia type 2A

is exacerbated by Fak^CG1

(Macagno et al., 2014)

is ameliorated by Fak^UAS.Tag:HA

(Macagno et al., 2014)

is exacerbated by Fak^5-SZ-3124

(Macagno et al., 2014)

Ret^MEN2B.UAS

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)

Ret^{UAS.Tag:LOV(VfAU1)}

ameliorates Parkinson's disease 6

modeled by Pink1^B9

(Ingles-Prieto et al., 2021)

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\RET^UAS.WT

P{UAS-hRET.WT}

Selected Drosophila transgenes

Allele

Transgene

Publicly Available Stocks

Ret^MEN2B.UAS

P{UAS-Ret.MEN2B}

Ret^{UAS.Tag:LOV(VfAU1)}

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

w¹¹¹⁸; P{GD45}v843

y¹ v¹; P{TRiP.JF01968}attP2

y¹ v¹; P{TRiP.HMC03102}attP40

Ret^HMC04143

P{TRiP.HMC04143}

y¹ v¹; P{TRiP.HMC04143}attP2

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

Ret^KO

amorphic allele - molecular evidence

ends-out gene targeting

Ret^LM1

amorphic allele - molecular evidence

CRISPR/Cas9

w^*/Dp(1;Y)y⁺, P{ActGFP}SH1; Ret^LM1

Ret^LM2

amorphic allele - molecular evidence

CRISPR/Cas9

Ret^LM3

amorphic allele - molecular evidence

CRISPR/Cas9

w^*; Ret^LM3/CyO, P{ActGFP}JMR1

References (5)

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