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General Information
Symbol
Dmel\fra4
Species
D. melanogaster
Name
FlyBase ID
FBal0057432
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
Associated Sequence Data
DNA sequence
Protein sequence
 
 
Progenitor genotype
Cytology
Nature of the lesion
Statement
Reference
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 ( 0 )
Disease
Evidence
References
Modifiers Based on Experimental Evidence ( 0 )
Disease
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References
Comments on Models/Modifiers Based on Experimental Evidence ( 0 )
 
Disease-implicated variant(s)
 
Phenotypic Data
Phenotypic Class
Phenotype Manifest In

commissure & embryo & axon

Detailed Description
Statement
Reference

In 33 out of 72 abdominal segments examined in fra3/fra4 third instar larvae, the LCh1 cap cell migrates ventrally instead of dorsally; in 14 of 33 segments the cap cell travels along the ventral midline (along the VChA and VChB organs) and morphology of cap cells is largely normal, while in the remaining 19 segments the LCh1 cap cell often migrates towards the LCh5 LA cell and then turns ventrally after contact with the LA cell and cap cell morphology is abnormal. Similar phenotypes are seen with the migrating VChB cap cell, where in 18 out of 72 mutant segments it does not reach or attach to the LA cell.

fra3/fra4 embryos show thinning of commissures in the central nervous system, with the EW axons failing to cross the midline in 30% of abdominal segments.

Levels of apoptosis are not increased in the thoracic and abdominal segments of the fra4 mutant ventral nerve cord.

fra3/fra4 mutants exhibit defects in Fas2-positive axons, including occasional breaks in longitudinal pathways, although the fascicles always remain ipsilateral.

fra3/fra4 mutants exhibit virtually complete loss of commissural fascicles of C4da neurons. Furthermore the terminal processes of C4da axons in fra3/fra4 mutants appear to lose the asymmetric orientation towards the midline.

fra3/fra4 embryos display display commissure loss. One of the predominant defects in fra3/fra4 mutants is thinning and missing posterior commissures, with nearly a quarter of segments showing this defect.

Fas2-positive fascicles tend to fuse together or form small gaps in fra3/fra4 embryos.

Defects characterised by Fas2-positive axons ectopically exiting the central nervous system (CNS) are not observed in fra3/fra4 mutant embryos.

Some hemisegments in fra3/fra4 embryos have ectopic glial cell clusters in the dorsal periphery.

In fra3/fra4 mutant embryos, dendritic targeting to the midline is abolished in MN-VO4-6 and MN-VO4/5 projecting neurons.

In fra3/fra4 mutant embryos, 63% of MN-LL1 dendritic arbors lack the normally pronounced intermediate dendritic arborisation, while targeting of MN-DA3 dendrites is not significantly affected. MN-LL1 has a clearly reduced innervation of the intermediate neuropile in 63-64% of cases.

fra4/fra6 mutant embryos have normal commissure formation and a mild EW axon crossing defect.

26% of fra3/fra4 embryos show defects in axon guidance in the Bolwig's nerve.

fra3/fra4 embryos show defects in the commissures of the central nervous system; 2% of anterior commissures are absent, 4% of anterior commissures are thin, 3% of posterior commissures are absent and 8% of posterior commissures are thin. 8% of segments fail to separate the anterior and posterior commissures correctly.

Heterozygous fra4 stage 16 embryos do not display abnormal midline crossing axon tract projections.

EW axons frequently fail to cross the midline in fra3/fra4 mutant embryos. The trajectories of the EG axons are unaffected in these mutants.

13% of segments have thin/missing commissures and 8% of segment have commissures with pathfinding errors in fra4/Df(2R)vg135 embryos. Breaks in the longitudinal connectives are seen in 10% of these embryos 23% of segments have thin/missing commissures and 13% of segment have commissures with pathfinding errors in fra4/fra4 embryos.

fra3/fra4 transheterozygote embryos show salivary gland guidance defects. Most mutants have salivary glands that lie parallel to the CNS midline as in wild type. However, in 4% of mutants, the glands curve laterally away from the midline and in 2% of mutants, the glands curve medially toward the midline.

fra3/fra4 embryos exhibit breaks in Con-positive commissural axons and longitudinal tracts.

dMP2 axons make pathfinding errors in fra3/fra4 mutant embryos, often extending laterally, turning anteriorly or stalling. Expression of fraΔC.Scer\UAS.T:Hsap\MYC under the control of Scer\GAL4605 in fra3/fra4 embryos results in abnormal spreading of the dMP2 growth cone over the region of induced ectopic NetB accumulation.

fra4 mutant clones in the eye show no discernable projection defects. fra4 mutant clones in the developing lamina are innervated abnormally. Wild type retinal fibers are incapable of innervating lamina target regions that lack fra function. Retinal fibers consistently avoid fra mutant patches and reroute to fra+ areas. Rerouting can occur in both the a-p and d-v axis. Incoming retinal fibers respect clonal boundaries.

The RP3 axon extends dorsally past and just adjacent to muscles 7 and 6 and then reached back to innervate them. RP3 neuron may extend into its normal muscle domain but fail to innervate muscles 7 and 6. The ISNb fails to innervate muscles 7 and 6. Scer\GAL4how-24B-mediated expression of NetAScer\UAS.cHa or NetBScer\UAS.cHa allows the axons of the transverse nerve to ectopically innervate muscles 7 and 6, loss of fra function suppresses this phenotype.

In fra3/fra4 embryos 12% of anterior commissures and 43% of posterior commissures in abdominal segments A1-A7 are thin or absent. Commissures that appear to have normal thickness are often less well organised than normal. Occasional breaks are also observed in the longitudinal tracts. A subset of motor axons exit the ventral CNS in the intersegmental nerve and extend dorsally, in fra3/fra4 embryos the axons often extend a colateral branch into an adjacent segment or make inappropriate contacts with dorsal muscles when they reach the dorsal muscle region.

External Data
Interactions
Show genetic interaction network for Enhancers & Suppressors
Phenotypic Class
Enhanced by
Statement
Reference

fra6/fra4 has abnormal neuroanatomy | embryonic stage phenotype, enhanceable by commE39/comm[+]

fra4 has abnormal neuroanatomy phenotype, enhanceable by Abl1/Abl[+]

fra4 has abnormal neuroanatomy phenotype, enhanceable by trio[+]/trioIMP159.4

fra4 has abnormal neuroanatomy phenotype, enhanceable by trio[+]/trioM89

fra4 has abnormal neuroanatomy phenotype, enhanceable by trio[+]/trioS036810

fra4 has abnormal neuroanatomy phenotype, enhanceable by Abl4/Abl[+]

NOT Enhanced by
Statement
Reference
Suppressed by
NOT suppressed by
Enhancer of
Statement
Reference

fra4/fra[+] is an enhancer of abnormal neuroanatomy | recessive phenotype of Nl1N-ts1

NOT Enhancer of
Suppressor of
NOT Suppressor of
Other
Phenotype Manifest In
Enhanced by
Statement
Reference

fra3/fra4 has EW neuron phenotype, enhanceable by robo2X123/robo2x135

fra6/fra4 has EW neuron phenotype, enhanceable by commE39/comm[+]

fra4 has symmetrical commissure phenotype, enhanceable by Abl1/Abl[+]

fra4 has symmetrical commissure phenotype, enhanceable by trio[+]/trioIMP159.4

fra4 has symmetrical commissure phenotype, enhanceable by trio[+]/trioM89

fra4 has symmetrical commissure phenotype, enhanceable by trio[+]/trioS036810

fra4 has symmetrical commissure phenotype, enhanceable by Abl4/Abl[+]

NOT Enhanced by
Suppressed by
NOT suppressed by
Enhancer of
NOT Enhancer of
Suppressor of
Statement
Reference
NOT Suppressor of
Other
Additional Comments
Genetic Interactions
Statement
Reference

robo2X123/robo2x135 strongly enhances the midline crossing defects seen in fra3/fra4 embryos: approximately 70% of EW neurons fail to cross the midline in the double mutant embryos.

Dscam05518 fra4 double mutants show a significant increase in apoptosis in the thoracic and abdominal segments of the ventral nerve cord compared to controls.

The Nl1N-ts1 pioneer axon phenotype is strongly enhanced by heterozygosity for fra4.

A fra4 mutant background suppresses the ectopic contralateral projections seen when Trim9Scer\UAS.T:Ivir\HA1 is expressed in v'ada neurons under the control of Scer\GAL4ppk.PG.

Over-expression of AblScer\UAS.cHa using Scer\GAL4insc-Mz1407 enhances the degree of thinning and missing posterior commissures in fra3/fra4 embryos, and many anterior commissures disappear. Large bundles of axons are observed ectopically exiting the central nervous system (CNS), often extending beyond the CNS/PNS boundary.

Pan-neural expression of AblKN.Scer\UAS under the control of Scer\GAL4insc-Mz1407 in fra3/fra4 embryos significantly increases the frequency of thin and missing posterior commissure defects.

Commissure formation is restored in fra3/fra4 mutants expressing both fraΔP1.Scer\UAS and AblScer\UAS.cHa under the control of Scer\GAL4insc-Mz1407.

Commissure formation is restored in fra3/fra4 mutants expressing both fraΔP2.Scer\UAS and AblScer\UAS.cHa under the control of Scer\GAL4insc-Mz1407.

Commissure formation is restored in fra3/fra4 mutants expressing both fraΔP3.Scer\UAS and AblScer\UAS.cHa under the control of Scer\GAL4insc-Mz1407.

Nearly a third of hemi-segments in fra3/fra4 embryos expressing Scer\GAL4insc-Mz1407>AblScer\UAS.cHa exhibit defects characterised by Fas2-positive axons ectopically exiting the central nervous system (CNS).

Less than 10% of fra3/fra4 embryos expressing Scer\GAL4insc-Mz1407>AblKN.Scer\UAS exhibit defects characterised by Fas2-positive axons ectopically exiting the central nervous system (CNS).

The commissural defects seen in fra4/fra6 embryos are enhanced in a heterozygous commE39/+ genetic background as shown by missing and thin commissures in many segments, as well as an increased frequency of non-crossing defects in a subset of of commissural neurons.

67% of Dscam05518/Dscam05518 fra4/fra4 embryos show defects in axon guidance in the Bolwig's nerve.

The penetrance of the axon guidance defect phenotype that is seen in the Bolwig's nerve of Dscam05518/Dscam05518 fra4/fra4 double mutant embryos is not increased by addition of Dscam3c02826/Dscam3c02826.

30% of Df(1)NP5/+ ; fra4/+ embryos show defects in axon guidance in the Bolwig's nerve.

22.5% of Dscam05518/+ ; fra4/+ embryos show defects in axon guidance in the Bolwig's nerve.

Dscam05518 fra4 embryos show defects in the commissures of the central nervous system; 9% of anterior commissures are absent, 24% of anterior commissures are thin, 5% of posterior commissures are absent and 39% of posterior commissures are thin. 51% of segments fail to separate the anterior and posterior commissures correctly.

fra3/fra4 Dscam3c02826 embryos show defects in the commissures of the central nervous system; 2% of anterior commissures are absent, 3% of anterior commissures are thin, 1% of posterior commissures are absent and 9% of posterior commissures are thin. 48% of segments fail to separate the anterior and posterior commissures correctly.

fra4 Abl4 embryos show defects in the commissures of the central nervous system; 14% of anterior commissures are absent, 24% of anterior commissures are thin, 16% of posterior commissures are absent and 24% of posterior commissures are thin. 19% of segments fail to separate the anterior and posterior commissures correctly.

Dscam05518 fra4 Dscam3c02826 embryos show defects in the commissures of the central nervous system; 39% of anterior commissures are absent, 51% of anterior commissures are thin, 36% of posterior commissures are absent and 55% of posterior commissures are thin. 5% of segments fail to separate the anterior and posterior commissures correctly.

Dscam05518 fra4 Abl4 embryos show defects in the commissures of the central nervous system; 98% of anterior commissures are absent, 2% of anterior commissures are thin and 100% of posterior commissures are absent.

One copy of fra4 weakly suppresses the detached posterior crossvein phenotype seen when DysdsRNA.NH2.Scer\UAS is expressed under the control of Scer\GAL4Act.PU.

One copy of fra4 moderately suppresses the detached posterior crossvein phenotype seen when DysdsRNA.C.Scer\UAS is expressed under the control of Scer\GAL4tub.PU but produces extra wing vein material.

One copy of fra4 weakly in a DysE6/+ background results in posterior crossvein defects.

Heterozygous fra4 partially suppresses the incorrect midline crossing phenotype of ventral nerve cord axons in embryos overexpressing Cdc42V12.Scer\UAS via Scer\GAL4ftz.ng.

Heterozygous fra4 partially suppresses the incorrect midline crossing phenotype of ventral nerve cord axons in embryos overexpressing Rac1V12.Scer\UAS via Scer\GAL4ftz.ng.

Expression of fra::roboScer\UAS.FΔC.T:Hsap\MYCunder the control of Scer\GAL4elav.PLu fails to rescue the fra3/fra4 axon guidance phenotypes.

Approximately 66% of fra4/Df(2R)en-SFX31 double mutants exhibit defects in axonal pathfinding. Stage 15 embryos display dramatic defects in ventral nerve cord architecture, with the posterior commissures missing or fused with the anterior commissures, and longitudinal tracts thinner. Nearly all the segments are affected in these embryos.

The frequency of the loss of commissure phenotype seen in Abl1/Abl4 embryos is not enhanced by fra4/+, but the frequency of commissures with pathfinding errors is increased in the fra4/+; Abl1/Abl4 embryos compared to Abl1/Abl4.

In mewM6/Y; fra3/fra4 double mutant embryos, the misguided salivary gland phenotype is modified, compared to that of each single mutant. Like fra3/fra4 mutants, the majority (75%) of misguided glands curve laterally, but levels of penetrance are high, similar to mewM6/Y single mutants. In sli2; fra3/fra4 double mutants, the penetrance of the salivary gland guidance defects is by 40% compared to sli2 single mutants.

A reduction in midline crossing is observed upon removal of two copies of the fra gene in Scer\GAL4elav-C155/Gα49BQ203L.Scer\UAS;fra3/fra4, from 48.10% of abdominal segments exhibiting midline crossover in Scer\GAL4elav-C155/Gα49BQ203L.Scer\UAS embryos to 5.3% in Scer\GAL4elav-C155/Gα49BQ203L.Scer\UAS;fra3/fra4 mutant embryos. Embryos of the genotype Scer\GAL4elav-C155/Gα49BQ203L.Scer\UAS and fra3/fra4 exhibit breaks in Con-positive commissural axons and longitudinal tracts, similar to Scer\GAL4elav-C155/Gα49BQ203L.Scer\UAS; fra3/fra4 embryos, indicating that Gα49B does not have an effect on the fra mutant phenotype.

Expression of NetBScer\UAS.cHa under the control of Scer\GAL4605 in fra3/fra4 embryos results in abnormal spreading of the dMP2 growth cone over the region of ectopic NetB expression.

Xenogenetic Interactions
Statement
Reference

Expression of Rnor\DccScer\UAS.T:Hsap\MYC under the control of Scer\GAL4eg-Mz360 rescues the midline crossing defects found in EW neurons in fra3/fra4 mutants.

Expression of Rnor\DccY1418F.Scer\UAS.T:Hsap\MYC under the control of Scer\GAL4eg-Mz360 rescues the midline crossing defects found in EW neurons in fra3/fra4 mutants.

Over-expression of Abl::Hsap\ABL1::Hsap\BCRP210.Scer\UAS using Scer\GAL4insc-Mz1407 enhances the degree of thinning and missing posterior commissures in fra3/fra4 embryos, and many anterior commissures disappear. Large bundles of axons are observed ectopically exiting the central nervous system (CNS), often extending beyond the CNS/PNS boundary. The anterior commissures, which are virtually unaffected in fra3/fra4 embryos, are thin or missing in 41% of segments.

Re-expression of fraScer\UAS.cKa in fra3/fra4 mutants reverts the phenotype back to that seen when Abl::Hsap\ABL1::Hsap\BCRP210.Scer\UAS is expressed alone under the control of Scer\GAL4insc-Mz1407 : fuzzy commissures.

Re-expression of fraScer\UAS.cKa in fra3/fra4 mutants reverts the phenotype back to that seen when AblScer\UAS.cHa is expressed alone under the control of Scer\GAL4insc-Mz1407 : normal anterior and posterior commissure formation.

In fra3/fra4 mutants expressing Scer\GAL4insc-Mz1407>Abl::Hsap\ABL1::Hsap\BCRP210.Scer\UAS, expression of fraΔP1.Scer\UAS is able tor revert the commissure loss seen in fra3/fra4 mutants. These mutants display fuzzy commissures.

In fra3/fra4 mutants expressing Scer\GAL4insc-Mz1407>Abl::Hsap\ABL1::Hsap\BCRP210.Scer\UAS, expression of fraΔP2.Scer\UAS is able tor revert the commissure loss seen in fra3/fra4 mutants. These mutants display fuzzy commissures.

In fra3/fra4 mutants expressing Scer\GAL4insc-Mz1407>Abl::Hsap\ABL1::Hsap\BCRP210.Scer\UAS, expression of fraΔP3.Scer\UAS restores commissure formation in fra3/fra4 mutants. The frequency of fuzzy commissures is also significantly reduced.

fra3/fra4 significantly reduces the frequency of ectopic axonal midline-crossovers resulting from the expression of Scer\GAL4insc-Mz1407>Abl::Hsap\ABL1::Hsap\BCRP210.Scer\UAS.

fra3/fra4 fails to reduce the frequency of ectopic axonal midline-crossovers resulting from the expression of Scer\GAL4insc-Mz1407>Abl::Hsap\ABL1::Hsap\BCRP210.Scer\UAS when fraScer\UAS.cKa is co-expressed.

fra3/fra4 fails to reduce the frequency of ectopic axonal midline-crossovers resulting from the expression of Scer\GAL4insc-Mz1407>Abl::Hsap\ABL1::Hsap\BCRP210.Scer\UAS when fraΔP1.Scer\UAS is co-expressed.

fra3/fra4 fails to reduce the frequency of ectopic axonal midline-crossovers resulting from the expression of Scer\GAL4insc-Mz1407>Abl::Hsap\ABL1::Hsap\BCRP210.Scer\UAS when fraΔP2.Scer\UAS is co-expressed.

fra3/fra4 significantly reduces the frequency of ectopic axonal midline-crossovers resulting from the expression of Scer\GAL4insc-Mz1407>Abl::Hsap\ABL1::Hsap\BCRP210.Scer\UAS when fraΔP3.Scer\UAS is co-expressed.

Nearly a third of hemi-segments in fra3/fra4 embryos expressing Scer\GAL4insc-Mz1407>Abl::Hsap\ABL1::Hsap\BCRP210.Scer\UAS exhibit defects characterised by Fas2-positive axons ectopically exiting the central nervous system (CNS).

The midline crossover phenotype caused expression of Ggal\MLCKct.Scer\UAS under the control of Scer\GAL4ftz.ng is partially suppressed by fra4/+.

Complementation and Rescue Data
Partially rescued by
Comments

Expression of fraScer\UAS.cOa.T:Hsap\MYC in all neurons, through expression under the control of Scer\GAL4elav.PLu, rescues EW midline crossing defects in fra3/fra4 mutants.

Expression of fra9YF.Scer\UAS.T:Hsap\MYC in all neurons, through expression under the control of Scer\GAL4elav.PLu, rescues EW midline crossing defects in fra3/fra4 mutants.

Expression of fraScer\UAS.cKa in C4da neurons under the control of Scer\GAL4ppk.PG partially rescues the axonal defects seen in fra3/fra4 mutants.

Expression of fraScer\UAS.cKa under the control of Scer\GAL4gcm.PU rescues the defects in interface glial cell migration seen in fra3/fra4 embryos.

Expression of fraScer\UAS.cKa under the control of Scer\GAL4MZ1580 weakly rescues the defects in interface glial cell migration seen in fra3/fra4 embryos.

The defects in interface glial cell migration seen in fra3/fra4 embryos are not rescued by expression of fraScer\UAS.cKa under the control of any one of Scer\GAL4repo, Scer\GAL4pros.PMG, Scer\GAL4elav.PU or Scer\GAL4Mz605.

Expression of fraScer\UAS.cKa under the control of Scer\GAL4eve.CQ2 rescues dendritic targeting to the midline in fra3/fra4 mutant MN-VO4-6 and MN-VO4/5 neurons.

Expression of fraScer\UAS.cKa under the control of Scer\GAL4eve.CQ2 selectively in MN-LL1 neurons in fra3/fra4 mutant embryos efficiently rescues dendritic targeting to the intermediate neuropile. Moreover, this manipulation leads to a greater proportion of dendritic branches innervating the intermediate neuropile.

Expression of fraScer\UAS.T:Hsap\MYC under the control of Scer\GAL4eg-Mz360 cell-autonomously rescues the EW guidance defects of fra3/fra4 embryos.

Expression of fraScer\UAS.T:Ivir\HA under the control of Scer\GAL4eg-Mz360 cell-autonomously rescues the EW guidance defects of fra3/fra4 embryos.

Expression of fraScer\UAS.cKa under the control of Scer\GAL415J2 does not rescue the dMP2 axonal phenotype of fra3/fra4 embryos. Expression of fraScer\UAS.cKa under the control of Scer\GAL4605 does rescue the dMP2 axonal phenotype of fra3/fra4 embryos.

Scer\GAL41407 induced expression of fraScer\UAS.cKa in fra3/fra4 embryos rescues the commissure phenotype, commissures form normally in abdominal segments A1-A7. ISN motor axons also innervate their targets at near wild type levels.

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References (30)