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General Information
Symbol
Dmel\Trpml1
Species
D. melanogaster
Name
FlyBase ID
FBal0221782
Feature type
allele
Associated gene
Associated Insertion(s)
Carried in Construct
Key Links
Nature of the Allele
Mutations Mapped to the Genome
 
Type
Location
Additional Notes
References
Comment:

Imprecise excision of the progenitor insertion, resulting in a 1.1kb deletion which removes nucleotides -456 to +641 relative to the Trpml translation start site.

Associated Sequence Data
DNA sequence
Protein sequence
 
 
Cytology
Nature of the lesion
Statement
Reference

Imprecise excision of the progenitor insertion, resulting in a 1.1kb deletion which removes nucleotides -456 to +641 relative to the trpml translation start site.

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
Modifiers Based on Experimental Evidence ( 1 )
Disease
Interaction
References
Comments on Models/Modifiers Based on Experimental Evidence ( 0 )
 
Disease-implicated variant(s)
 
Phenotypic Data
Phenotypic Class
Phenotype Manifest In
Detailed Description
Statement
Reference

Mature eggs from Trpml1 homozygous females show similar incidence of calcium waves as heterozygous controls upon in vitro egg activation.

Trpml1 individuals are unable to clear bacteria after injection of the non-pathogenic bacteria, E. coli, as compared to equally infected heterozygous controls.

Trpml1 mutant third instar larvae show dramatic enlargement of lysosomes (marked by Lysotracker) in the somatic muscles.

Trpml1 mutant adults show normal preference for less solid sucrose-agarose food than a harder one (higher agarose conc., same sucrose content) one in a two-way food choice assay.

Trpml1/Trpml1 third instar larvae display fewer neuromuscular junction boutons compared to wild-type controls, but the bouton morphology remains normal.

Trpml1/Trpml2 transheterozygous third instar larvae display fewer neuromuscular junction boutons compared to wild-type controls.

Trpml1/Df(3L)Exel6135 third instar larvae display fewer neuromuscular junction boutons compared to wild-type controls.

Supplementing food with ML-SA1 does not restore normal synaptic growth (number of neuromuscular junction boutons) in Trpml1 homozygous larvae.

Raising Trpml1 mutant larvae on a protein-rich diet does not alleviate the synaptic growth defects and the number of neuromuscular junction boutons in Trpml1 third instar larvae remains decreased compared to wild-type controls.

Raising Trpml1 mutant larvae on a protein-rich diet supplemented with the ALK inhibitor CH5424802 alleviates the synaptic growth defects and the decreased number of neuromuscular junction boutons characteristic for Trpml1 third instar larvae is restored compared to controls.

Raising Trpml1 mutants on a protein-rich diet supplemented with the ALK inhibitor CH5424802 increases the number of adults eclosing from pupal cases compared to Trpml1 mutant controls raised on protein-rich diet alone.

The gustatory aversion of mutant flies to 6mM camphor in a two way-choice test is not significantly different from that seen in wild-type flies.

trpml1 mutant fat body cells from wandering third instar larvae contain an increased number of autophagosomes and amphisomes compared to controls. The fat body cells also contain fewer and smaller lysosomes. The cells accumulate large single-membrane bound multivesicular bodies (MVBs)/amphisomes, many of which are touching lysosomes, apparently unable to go fusion; these are referred to as "fusion clamped" vesicles. Pairs of "fusion clamped" lysosomes are also seen.

The volume of LysoTracker-positive vesicles is increased in trpml1 mutant larval fat body cells. The increase is most pronounced in second instar larvae, but is still significant at the third instar stage. This phenotype is suppressed when the larvae are fed protein-rich yeast paste, or if the fat body is treated with thapsigargin, which blocks the sarcoplasmic/endoplasmic reticulum calcium ATPase pump.

trpml1 mutant adult photoreceptor cells show a dramatic elevation in the number of both multivesicular bodies (MVBs) and lysosomes, as well as accumulation of autophagosomes. The number of amphisomes is also increased. Despite these increases, the number of autolysosomes is not significantly different from wild type and the ratio of MVBs to autolysosomes is 10 fold higher in trpml1 mutant cells compared to controls. The number of MVBs touching lysosomes ("fusion-clamped vesicles") is significantly higher than in wild type.

The half-maximal time to pupation is increased compared to controls in trpml1 mutants, and this phenotype is rescued when the larvae are fed protein-rich yeast paste.

Less than 10% of trpml1 mutants eclose from the pupal cases. This lethality is significantly rescued when the flies are fed a high-protein diet. Lethality is also rescued when the larvae are fed food that has been supplemented with tryptone. Supplementation with sucrose has no effect on lethality. Feeding the larvae the TORC1 inhibitor Rapamycin enhances lethality when flies are reared on normal food, and suppresses the rescuing effect seen when flies are fed high-protein yeast paste.

trpmlc05523/trpml1 adult escapers have a 100% penetrant crumpled wing phenotype.

trpml1/Df(3L)Exel6135 adult escapers show normal baseline excitatory junctional current amplitudes at the neuromuscular junction at both pH 5.75 and under reduced Mg[2+] conditions.

Mutant adults show normal avoidance of 1% citronellal in a direct airborne repellent test (DART) assay.

trpml1 mutants retain a preference for 18[o]C (i.e. are thermotactic).

5 day old trpml1 adult escapers show a significantly reduced locomotor activity compared to controls. Homozygous 5 day old adult escapers show reduced climbing ability compared to controls in a negative geotaxis assay, and by 21 days after eclosion, negative geotaxis is nearly eliminated in the mutant flies.

21 day old trpml1/Df(3L)ED228 and trpml1/Df(3L)Exel6135 adult escapers show almost complete elimination of climbing ability in a negative geotaxis assay.

Ommatidia of newly eclosed trpml1 escapers contain the full set of rhabdomeres. However, a significantly lower fraction of ommatidia (53.8 +/- 9.9%) retain all seven rhabdomeres in 21 day old trpml1 flies compared to control flies of the same age (100% of ommatidia have 7 rhabdomeres in controls). The loss of rhabdomeres seen the trpml1 flies is partially suppressed if the flies are reared in the dark.

The brains of young trpml1 adults show minimal TUNEL staining, but the brains of 21 day old trpml1 adults show increased TUNEL staining. The brains of 21 day old trpml1 adults show a significant elevation in the accumulation of both early apoptotic cells and late apoptotic/necrotic cells compared to controls.

Photoreceptor cell bodies of 21 day old trpml1 adults have 6.5-fold more cytoplasmic inclusions than wild type. The inclusions vary in diameter from 0.2-1.0μm and consist of multilamellar and multivesicular bodies. This accumulation of cytoplasmic inclusions in the mutant flies is age dependent.

There is a small but significant increase in the number of mitochondria in the photoreceptor cell bodies of 21 day old trpml1 adults. However, there is a 4-fold decrease in the intensity of Mitotracker-orange GM-H2TMRos staining, indicating accumulation of damaged mitochondria.

21 day old trpml1 adults have approximately 40% higher hydrogen peroxide levels compared to controls.

trpml1 adults remain immobilised longer than wild type after exposure to CO[[2]] anesthesia.

The amplitude of the excitatory junctional potential (EJP) at the neuromuscular junction is decreased approximately 50% in trpml1 third instar larvae compared to controls.

External Data
Interactions
Show genetic interaction network for Enhancers & Suppressors
Phenotypic Class
NOT Enhanced by
Suppressed by
Statement
Reference
NOT suppressed by
Suppressor of
Other
Phenotype Manifest In
NOT Enhanced by
Suppressed by
NOT suppressed by
Enhancer of
Statement
Reference
Suppressor of
Other
Additional Comments
Genetic Interactions
Statement
Reference

The late pupal lethality observed in animals expressing AMPKαJF01951 under the control of Scer\GAL4Act.PU can be partially rescued by combination with either Trpml1 or Trpml2.

The pupal-stage lethality of either hemizygous AMPKα1 or AMPKα3 males can be partially rescued by combination with either Trpml1 or Trpml2.

Ectopic expression of RagA-BT16N.Scer\UAS under the control of the Scer\GAL4elav-C155 driver does not cause further decrease in the number of neuromuscular junction (NMJ) boutons in the already NMJ boutons-deficient Trpml1 mutant third instar larvae.

Ectopic expression of RagA-BQ61L.Scer\UAS under the control of the Scer\GAL4elav-C155 or Scer\GAL4nSyb.PS driver fully restores the decreased number of neuromuscular junction boutons characteristic for the Trpml1 mutant third instar larvae.

Ectopic expression of RagA-BQ61L.Scer\UAS under the control of the Scer\GAL4elav-C155 driver in the Trpml1 mutant background significantly increases the proportion of adults that eclose from pupal cases compared to the Trpml1 mutants.

Ectopic expression of AMPKαT184D.Scer\UAS under the control of the Scer\GAL4elav-C155 driver does not cause further decrease in the number of neuromuscular junction (NMJ) boutons in the already NMJ boutons-deficient Trpml1 mutant third instar larvae.

Ectopic expression of AMPKαK56R.Scer\UAS under the control of the Scer\GAL4elav-C155 driver does not restore the decreased number of neuromuscular junction boutons characteristic for the Trpml1 mutant third instar larvae.

Trpml1/+,bsk1/+ double heterozygotes show decreased number of NMJ boutons in third instar larvae compared to either Trpml1/+ or bsk1/+ single heterozygotes.

Trpml1/+;wnd3/+ double heterozygotes show decreased number of NMJ boutons in third instar larvae compared to either Trpml1/+ or wnd3/+ single heterozygotes.

Ectopic expression of hiwScer\UAS.fl under the Scer\GAL4elav-C155 driver in the Trpml1/+ heterozygous background causes a decrease in the number of neuromuscular junction boutons in third instar larvae compared to controls.

Supplementing food with ML-SA1 (ML-synthetic agonist) does restore normal synaptic growth (number of neuromuscular junction boutons) in third instar Trpml1/+ heterozygous larvae expressing hiwScer\UAS.fl under the Scer\GAL4elav-C155 driver.

hiwND8;Trpml1 double mutant larvae do not show the increase in number of neuromuscular junction boutons characteristic for the hiwND8 single mutants.

Trpml1/+,cln3ΔMB1/+ double heterozygotes show decreased number of NMJ boutons in third instar larvae compared to either Trpml1/+ or cln3ΔMB1/+ single heterozygotes.

Expression of RagA-BT16N.Scer\UAS under the control of the Scer\GAL4elav-C155 driver in Trpml1 mutant larvae raised on a protein-rich diet supplemented with the ALK inhibitor CH5424802 precludes the alleviation of the synaptic growth defects and the decreased number of neuromuscular junction boutons characteristic for Trpml1 third instar larvae remains low.

Expression of RagA-BQ61L.Scer\UAS under the control of Scer\GAL4Cg.PA suppresses the increase in Lysotracker-positive vesicle volume seen in trpml1 mutant fat body cells.

Expression of RhebScer\UAS.cUa under the control of Scer\GAL4Cg.PA suppresses the increase in Lysotracker-positive vesicle volume seen in trpml1 mutant fat body cells.

Expression of RagA-BT16N.Scer\UAS under the control of Scer\GAL4Cg.PA does not enhance the increase in Lysotracker-positive vesicle volume seen in trpml1 mutant fat body cells.

Feeding larvae high-protein yeast paste does not suppress the pupal lethality seen in Thor2 trpml1 double mutants. The addition of Rapamycin also fails to suppress the lethality.

Xenogenetic Interactions
Statement
Reference

trpml1 enhances the rate of age-dependent degeneration of photoreceptors that is caused by expression of Hsap\HDGMR.Q120.

The lethality of trpml1 homozygotes and the locomotor defects of trpml1 homozygous adult escapers is suppressed by expression of Hsap\HSPA1LScer\UAS.cWa under the control of either Scer\GAL4Act5C.PI or Scer\GAL4elav-C155.

Complementation and Rescue Data
Comments

The reduction in the number of neuromuscular junction boutons characteristic for Trpml1 mutant third instar larvae is fully rescued by combination with Trpml+tVa.

The crumpled wing phenotype seen in trpmlc05523/trpml1 adult escapers is completely rescued by trpml+tVa.

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Mutant
Wild-type
Stocks (4)
Notes on Origin
Discoverer
External Crossreferences and Linkouts ( 0 )
Synonyms and Secondary IDs (3)
References (17)