microPublication Biology 2578-9430 Caltech Library 10.17912/micropub.biology.002429 new finding phenotype data genotype data drosophila The serendipitous discovery of thoracic malformations in Lysine ketoglutarate reductase/saccharopine dehydrogenase mutants of Drosophila melanogaster Cook Kevin R. Conceptualization Funding acquisition Investigation Writing - original draft Writing - review & editing 1 § Bloomington Drosophila Stock Center, Department of Biology, Indiana University, Bloomington, IN, United States Maggert Keith A. Correspondence to: Kevin R. Cook ( kercook@iu.edu )

The authors declare that there are no conflicts of interest present.

 26 10 2026 2026 2026 10.17912/micropub.biology.002429 14 9 2026 4 10 2026 14 10 2026 Copyright: © 2026 by the authors 2026 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

A remarkable series of coincidences led the author to show that mutations in a Drosophila melanogaster gene encoding a protein responsible for degrading lysine and regulating ecdysone-induced histone methylation are associated with abnormal morphogenesis of the dorsal thorax. Specifically, loss-of-function mutations in the Lkrsdh gene, which encodes the Lysine ketoglutarate reductase/saccharopine dehydrogenase protein, result in loss of the scutoscutellar sulcus, the hingelike cuticular groove between the two major divisions of the fly thorax.

This work was supported by National Institutes of Health grant P40 OD018537 and the Kathy Matthews Endowment.

(A) Dorsal view of a wild type ( Canton-S ) fly showing the indentation of the dorsal thorax between the scutum and scutellum forming the scutoscutellar sulcus. The normal position of the sulcus is marked by arrowheads in all panels. (B) Dorsal view of an Lkrsdh mutant ( Lkrsdh CR70173-TG4.0 /Df(2L)ED12527 ) showing near absence of the sulcus. There is a smooth transition from the scutum to the scutellum rather than a deep groove. (C) Lateral view of the same fly to demonstrate the rounded, “grooveless” profile. The arrow points to a small clot from hemolymph leakage. As in grooveless mutants, leakage in Lkrsdh mutants typically occurs in three positions (this position near the humeral bristles, slightly dorsal and posterior to the sternopleural bristles and/or at the lateral ends of the scutoscutellar sulcus), but clots are usually larger than the one depicted here. (D and E) Dorsal views of other individuals with the same genotype showing that the cuticular area where the sulcus would normally form can sometimes appear crumpled and distorted. In flies with this phenotype, the thoracic profiles are still more rounded than the profiles of normal flies. This phenotype also appears in grooveless ( gvl ) mutants, though it was not mentioned by Cook and Mauthner (2026). F. Newly sequenced Lkrsdh alleles. The top lines show the positions of deletions in terms of Release 6 genomic coordinates. In two alleles, extra nucleotides were introduced at the breakpoint junctions by DNA repair processes. For the first four alleles, the bottom lines show N-terminal amino acids remaining from the normal sequences followed by novel residues introduced by frame-shifted translation. For Lkrsdh Δ163 , the bottom line shows replacement of 61 amino acids of the normal sequence with FFFFFHF. (Note that panel A was recycled from Cook and Mauthner (2026).)

Description

My colleague Stephanie Mauthner and I recently reported (Cook and Mauthner 2026) that homozygous mutations in the fourth chromosome gene grooveless ( gvl , formerly CG31997 ) reduce or eliminate the scutoscutellar sulcus—the transverse cuticular crease separating the larger subdivision of the notum, the scutum, from the smaller subdivision, the scutellum ( Figure 1A ). These mutations also cause hemolymph leakage from the thorax at lower penetrance. The gvl gene encodes a protein with a single von Willibrand factor type C (SVWC) domain, likely involved in binding other proteins, and a cell export signal, but no other known protein motifs (Sheldon et al. 2007). SVWC proteins appear to be restricted to arthropods, but the biological functions of few of these proteins have been studied in detail (Labropoulou et al. 2024).

At the same time we were characterizing gvl mutations, I was working on an unrelated project involving the Lkrsdh gene, which encodes the Lysine ketoglutarate reductase/saccharopine dehydrogenase protein responsible for two enzymatic steps in lysine degradation (Lkr activity in the N-terminal half converts lysine to saccharopine and Sdh activity in the C-terminal half converts saccharopine to alpha-aminoadipic semialdehyde; this bifunctional protein is also called aminoadipate semialdehyde synthase (St. Clair et al. 2017; Tan et al. 2023)). At least in Drosophila, Lkrsdh protein also inhibits ecdysone-induced methylation of histone H3 (Cakouros et al. 2008). In an effort to map a mutation that interacts with Lkrsdh mutations, I had generated more than a hundred chromosomes carrying a transposon disrupting the Lkrsdh gene ( Mi{ET1}Lkrsdh MB01942 ) linked to a variety of chromosomal deletions, transposon insertions and point mutations located proximal to Lkrsdh . When I combined 45 of these “double-mutation” chromosomes in various pairwise combinations in flies via crosses, I was surprised to see the same phenotypes I was seeing in gvl mutants: shallow scutoscutellar sulci in crosses with all 45 chromosomes and hemolymph leakage in crosses with 32 of them. To my knowledge, these phenotypes (Figure 1) had never been associated with any gene besides gvl and two other genes ( ascute and ascutex ) identified by Calvin Bridges (Bridges 1935; Bridges and Morgan 1923; Morgan et al. 1925), so it was an amazing coincidence to see them in a different context at the same time I was working with gvl mutants!

The causative mutation must have been present on the Mi{ET1}Lkrsdh MB01942 chromosome used to make the double-mutation chromosomes. For it to have been homozygosed in all the crosses described above, it must lie distal to the y + -marked Mi{MIC}MI04503 transposon insertion in polytene subdivision 30B, because I screened for single crossovers between the cis -linked insertions Mi{ET1}Lkrsdh MB01942 and Mi{MIC}MI04503 to eliminate Mi{MIC}MI04503 and place the deletions, insertions and mutations on the same chromosome as Mi{ET1}Lkrsdh MB01942 . To identify this gvl -like mutation, I combined one of the double-mutation chromosomes ( Mi{ET1}Lkrsdh MB01942 Df(2L)Exel8022 ) with the 54 tiling chromosomal deficiencies from the Bloomington Deficiency Kit that remove 30B to the 2L tip (see Reagents Table). In aggregate, these deficiencies removed 2,983 of the 3,010 genes distal to Mi{MIC}MI04503 . I found two overlapping deficiencies, Df(2L)BSC142 and Df(2L)BSC233, that failed to complement the mutation. With crosses of the same double-mutation chromosome to an additional seven deficiencies (see Reagents Table), I further narrowed the region with the mutation to the overlap of Df(2L)ED12527 and Df(2L)ED499 . Much to my surprise, one of the four genes within this overlap was Lkrsdh itself! These deficiencies also failed to complement a sampling of six additional double-mutation chromosomes.

To identify the mutated gene in this small, four-gene region, I complementation tested seven double-mutation chromosomes against mutations in three of the four genes ( Lkrsdh , lncRNA:CR44825 , Herp and r2d2 ) as well as mutations in the genes immediately flanking this region ( CG7149 and Cdc14 ) (see Reagents Table). Remarkably, I saw that the only noncomplementing mutation was one in Lkrsdh ( Lkrsdh CR70173-TG4.0 ; Figure 1)! Obviously, the Mi{ET1}Lkrsdh MB01942 insertion on the double-mutation chromosomes was responsible for the grooveless phenotypes rather than a mutation linked to it.

I have now seen the grooveless phenotypes in complementation crosses with six additional Lkrsdh alleles. Four alleles ( Lkrsdh Δ11 , Lkrsdh Δ16 , Lkrsdh Δ17 and Lkrsdh Δ17-1 ) are CRISPR-induced, frameshift mutations generated in screens by Arthur Luhur and Jason Tennessen ( Figure 1F ). These crosses exhibited phenotypic penetrance and expressivity similar to the crosses described above. These four mutations are positioned to truncate the Lkrsdh protein and eliminate domains necessary for both Lkr and Sdh activities as well as the protein region that binds to the ecdysone receptor EcR in regulating histone methylation (Cakouros et al. 2008; Letunic and Bork 2026; Paysan-Lafosse et al. 2025). Lkr activity requires two domains: a catalytic domain and a domain that binds NAD+. The Lkr catalytic domain is likely intact in proteins produced by all four alleles (assuming the truncated proteins are stable), but its activity depends on the domain for binding NAD+, which would be absent—strongly suggesting these four alleles are amorphic. The fifth allele is the original Lkrsdh mutation, Lkrsdh 1 , which was previously called lysine 1 (Grell 1961; St. Clair et al. 2017). Interestingly, the scutoscutellar phenotype shows weak penetrance and expressivity in genotypes involving Lkrsdh 1 and hemolymph leakage was rare, suggesting that Lkrsdh 1 is hypomorphic. Lkrsdh 1 is a complex chromosomal rearrangement deleting the normal translation start site, inserting repetitive sequences before the seventh codon and introducing an indel (St. Clair et al. 2017), but my phenotypic results and results presented by St. Clair et al. showing an 80% reduction in transcription suggest there is residual gene expression—likely initiated from a transcription start site within the insertion. The presence of a methionine codon within the inserted sequences near the Lkrsdh coding sequences suggests that a variant protein is produced with a shorter, novel N-terminus. The sixth allele ( Lkrsdh Δ163 ) also appears to be hypomorphic. It came from one of the CRISPR screens mentioned above and consists of 183 bp in the region encoding the Lkr activity replaced by a thymidine-rich sequence (likely TTTTTTTTTTTTTTCCATTTT) that has proved difficult to sequence consistently. The hypomorphic phenotypes suggest the substituted sequence has the appropriate number of thymidines to allow in-frame translation of a variant Lkrsdh protein ( Figure 1F ) with a disrupted Lkr domain but intact Sdh and EcR-binding domains.

Flexion between the scutum and scutellum at the scutoscutellar sulcus is part of normal flight (Boettinger and Furshpan 1952; Miyan and Ewing 1985), but, similar to gvl mutants (Cook and Mauthner, 2026), I saw that Lkrsdh mutants ( Lkrsdh CR70173-TG4.0 /Df(2L)ED12527 ) with strong grooveless phenotypes are capable of flight. It seems likely that the thoracic malformations in gvl and Lkrsdh mutants affect flight efficiency, but in neither case has the details of flight mechanics been examined.

I do not know the developmental basis of “groovelessness”. Shallow scutoscutellar sulci and hemolymph leakage could be related to weak or improperly timed flight muscle contractions during pupal development, altered cuticle formation during metamorphosis, or both. Since many biological processes underlie muscle and cuticle development, groovelessness may be a relatively common mutant phenotype. The shallow sulcus phenotype may simply have escaped notice most of the time because it is fairly subtle. (I doubt I would have noticed it in Lkrsdh mutants if I had not been working with gvl mutants.) Indeed, there may be no close functional relationship between Lkrsdh protein and the secreted SVWC protein encoded by gvl. Currently, it is impossible to say if the grooveless phenotypes in Lkrsdh mutants are attributable to the widespread effects of increased lysine on metabolic processes (St. Clair et al. 2017), to the widespread effects of misregulating ecdysone-dependent processes on development (Morrow and Mirth 2024), or a mixture of both.

Methods

The stocks used in complementation tests are listed in the Reagents Table. More information about these stocks may be obtained via the website for the Bloomington Drosophila Stock Center (https://bdsc.indiana.edu/). Genetic nomenclature and gene models reflect FlyBase release 2026_03 (Öztürk-Çolak et al. 2024). DNA was extracted from frozen samples of adult flies using standard protocols and sequenced as single-end reads on the Ultima Genomics platform by the University of Minnesota Model Organism Sequencing Service (https://genomics.umn.edu/service/model-organism-sequencing).

 Reagents

Stock number

Genotype

RRID or source

Deficiency Kit stocks

90

Df(2L)C144, dpp d-ho ed 1 /In(2LR)Gla, wg Gla-1 PPO1 Bc Egfr E1

RRID:BDSC_90

744

Df(2L)M24F-B/SM1

RRID:BDSC_744

3084

Df(2L)ast2/SM1

RRID:BDSC_3084

3548

Df(2L)al, ds al /In(2L)Cy, Duox Cy

RRID:BDSC_3548

5330

Df(2L)ed1/CyO; P{ry +t7.2 =ftz-lacC}1

RRID:BDSC_5330

6338

Df(2L)BSC6, dpy ov1 cn 1 /SM6a

RRID:BDSC_6338

6507

y 1 w * ; Df(2L)drm-P2, P{w +mC =lacW}ND-PDSW k10101 /SM6b

RRID:BDSC_6507

6648

Df(2L)dpp d14 /In(2LR)Gla, wg Gla-1

RRID:BDSC_6648

7144

Df(2L)BSC37, dpp EP2232 /CyO

RRID:BDSC_7144

7492

w 1118 ; Df(2L)Exel6005, P{w +mC =XP-U}Exel6005/CyO

RRID:BDSC_7492

7495

w 1118 ; Df(2L)Exel6009, P{w +mC =XP-U}Exel6009/CyO

RRID:BDSC_7495

7497

w 1118 ; Df(2L)Exel6011, P{w +mC =XP-U}Exel6011/CyO

RRID:BDSC_7497

7744

w 1118 ; Df(2L)Exel6277, P{w +mC =XP-U}Exel6277/CyO

RRID:BDSC_7744

7783

w 1118 ; Df(2L)Exel7011/CyO

RRID:BDSC_7783

7807

w 1118 ; Df(2L)Exel7034/CyO

RRID:BDSC_7807

8673

w 1118 ; Df(2L)BSC107/SM6a

RRID:BDSC_8673

8674

w 1118 ; Df(2L)BSC109/CyO

RRID:BDSC_8674

8835

w 1118 ; Df(2L)BSC110/CyO

RRID:BDSC_8835

8836

w 1118 ; Df(2L)BSC111/CyO

RRID:BDSC_8836

8901

w 1118 ; Df(2L)ED19, P{w +mW.Scer\FRT.hs3 =3'.RS5+3.3'}ED19/SM6a

RRID:BDSC_8901

8906

w 1118 ; Df(2L)ED678, P{w +mW.Scer\FRT.hs3 =3'.RS5+3.3'}ED678/SM6a

RRID:BDSC_8906

8908

w 1118 ; Df(2L)ED94, P{w +mW.Scer\FRT.hs3 =3'.RS5+3.3'}ED94/SM6a

RRID:BDSC_8908

9176

w 1118 ; Df(2L)ED136, P{w +mW.Scer\FRT.hs3 =3'.RS5+3.3'}ED136/SM6a

RRID:BDSC_9176

9270

w 1118 ; Df(2L)ED250, P{w +mW.Scer\FRT.hs3 =3'.RS5+3.3'}ED250/In(2L)Cy L t R In(2R)Cy, Duox Cy amos Roi-1

RRID:BDSC_9270

9341

w 1118 ; Df(2L)ED385, P{w +mW.Scer\FRT.hs3 =3'.RS5+3.3'}ED385/SM6a

RRID:BDSC_9341

9343

w 1118 ; Df(2L)ED334, P{w +mW.Scer\FRT.hs3 =3'.RS5+3.3'}ED334/SM6a

RRID:BDSC_9343

9353

w 1118 ; Df(2L)ED5878, P{w +mW.Scer\FRT.hs3 =3'.RS5+3.3'}ED5878/SM6a

RRID:BDSC_9353

9502

w 1118 ; Df(2L)BSC142/CyO

RRID:BDSC_9502

9560

w 1118 ; Df(2L)BSC169/CyO

RRID:BDSC_9560

9600

w 1118 ; Df(2L)BSC165/CyO

RRID:BDSC_9600

9605

w 1118 ; Df(2L)BSC172/CyO

RRID:BDSC_9605

9610

w 1118 ; Df(2L)BSC180/CyO

RRID:BDSC_9610

9615

w 1118 ; Df(2L)BSC188/CyO

RRID:BDSC_9615

9631

w 1118 ; Df(2L)BSC204/CyO

RRID:BDSC_9631

9704

w 1118 ; Df(2L)BSC227/CyO

RRID:BDSC_9704

9708

w 1118 ; Df(2L)BSC233/CyO

RRID:BDSC_9708

23676

w 1118 ; Df(2L)BSC291/CyO

RRID:BDSC_23676

23677

w 1118 ; Df(2L)BSC292/CyO

RRID:BDSC_23677

23680

w 1118 ; Df(2L)BSC295/CyO

RRID:BDSC_23680

24118

w 1118 ; Df(2L)ED105, P{w +mW.Scer\FRT.hs3 =3'.RS5+3.3'}ED105/SM6a

RRID:BDSC_24118

24123

w 1118 ; Df(2L)ED247, P{w +mW.Scer\FRT.hs3 =3'.RS5+3.3'}ED247/SM6a

RRID:BDSC_24123

24124

w 1118 ; Df(2L)ED7853, P{w +mW.Scer\FRT.hs3 =3'.RS5+3.3'}ED7853/SM6a

RRID:BDSC_24124

24127

w 1118 ; Df(2L)ED489, P{w +mW.Scer\FRT.hs3 =3'.RS5+3.3'}ED489/SM6a

RRID:BDSC_24127

24132

w 1118 ; Df(2L)ED629, P{w +mW.Scer\FRT.hs3 =3'.RS5+3.3'}ED629/SM6a

RRID:BDSC_24132

24378

w 1118 ; Df(2L)BSC354/CyO

RRID:BDSC_24378

24626

w 1118 ; Df(2L)ED50001, P{w +mW.Scer\FRT.hs3 =3'.RS5+3.3'}ED50001/SM6a

RRID:BDSC_24626

24652

w 1118 ; Df(2L)ED441, P{w +mW.Scer\FRT.hs3 =3'.RS5+3.3'}ED441/SM6a

RRID:BDSC_24652

24958

w 1118 ; Df(2L)BSC454/SM6a

RRID:BDSC_24958

24959

w 1118 ; Df(2L)BSC455/SM6a

RRID:BDSC_24959

25743

w 1118 ; Df(2L)BSC653/SM6a

RRID:BDSC_25743

26540

w 1118 ; Df(2L)BSC688, P+PBac{w +mC =XP3.WH3}BSC688/SM6a

RRID:BDSC_26540

26544

w 1118 ; Df(2L)BSC692, P+PBac{w +mC =XP3.RB5}BSC692/SM6a

RRID:BDSC_26544

27381

w 1118 ; Df(2L)BSC810/SM6a

RRID:BDSC_27381

94697

w 1118 ; Df(2L)ED4651/SM6a

RRID:BDSC_94697

Additional deficiency stocks

9274

w 1118 ; Df(2L)ED499, P{w +mW.Scer\FRT.hs3 =3'.RS5+3.3'}ED499/SM6a

RRID:BDSC_9274

9616

w 1118 ; Df(2L)BSC189/CyO

RRID:BDSC_9616

9617

w 1118 ; Df(2L)BSC190/CyO

RRID:BDSC_9617

9618

w 1118 ; Df(2L)BSC191/CyO

RRID:BDSC_9618

9619

w 1118 ; Df(2L)BSC192/CyO

RRID:BDSC_9619

24128

w 1118 ; Df(2L)ED501, P{w +mW.Scer\FRT.hs3 =3'.RS5+3.3'}ED501/SM6a

RRID:BDSC_24128

24129

w 1118 ; Df(2L)ED12527, P{w +mW.Scer\FRT.hs3 =3'.RS5+3.3'}ED12527/SM6a

RRID:BDSC_24129

Mutations tested in the Lkrsdh region

14288

y 1 w 67c23 ; P{y +mDint2 w BR.E.BR =SUPor-P}CG7149 KG06170

RRID:BDSC_14288

14997

y 1 w 67c23 ; P{y +mDint2 w +mC =EPgy2}r2d2 EY00028

RRID:BDSC_14997

16450

y 1 w 67c23 ; P{y +mDint2 w +mC =EPgy2}Cdc14 EY10303

RRID:BDSC_16450

17058

w 1118 ; P{w +mC =EP}Herp EP2450

RRID:BDSC_17058

20640

y 1 w 67c23 ; P{y +mDint2 w +mC =EPgy2}CG7149 EY10883

RRID:BDSC_20640

29231

w 1118 ; Mi{GFP E.3xP3 =ET1}r2d2 MB11618 /SM6a

RRID:BDSC_29231

32068

P{GMR-w.RNAi}13D; P{ry +t7.2 =neoFRT}40A r2d2 S165fsX

RRID:BDSC_32068

37074

y 1 w * ; Mi{y +mDint2 =MIC}Herp MI03683

RRID:BDSC_37074

54575

y 1 w * ; r2d2 1 P{ry +t7.2 =neoFRT}40A/CyO, amos Roi-1

RRID:BDSC_54575

60537

y 1 w 67c23 ; Mi{PT-GFSTF.2}Herp MI03683-GFSTF.2

RRID:BDSC_60537

79333

y 1 w * ; TI{GFP 3xP3.cLa =CRIMIC.TG4.2}Cdc14 CR00871-TG4.2

RRID:BDSC_79333

92724

y 1 w * ; TI{GFP 3xP3.cLa =CRIMIC.TG4.0}Lkrsdh CR70173-TG4.0 /SM6a

RRID:BDSC_92724

600152

w * ; Df(2L)LanB1/CyO, P{w +mC =GAL4-Kr.C}DC3, P{w +mC =UAS-GFP.S65T}DC7

RRID:BDSC_600152

Additional Lkrsdh mutations tested

692

Lkrsdh 1 rc 1 ; ss 1

RRID:BDSC_692

101560

wg Sp-1 Lkrsdh 1 rc 1 J 1 /SM1

Kyoto Stock Center

607941

w 1118 ; Lkrsdh Δ11 /CyO

RRID:BDSC_607941

w 1118 ; Lkrsdh Δ16 /CyO

Jason Tennessen

607942

w 1118 ; Lkrsdh Δ17 /CyO

RRID:BDSC_607942

w 1118 ; Lkrsdh Δ17-1 /CyO

Jason Tennessen

w 1118 ; Lkrsdh Δ163 /CyO

Jason Tennessen

Stock used for the photograph of a normal scutoscutellar sulcus

64349

Canton-S

RRID:BDSC_64349

I thank Jason Tennessen, Sophie Fleck and Arthur Luhur of Indiana University for stocks with unpublished Lkrsdh alleles and for helpful discussions and my colleagues at the Bloomington Drosophila Stock Center for their support. Stocks were obtained from the Department of Drosophila Genomics and Genetic Resources of the Kyoto Institute of Technology (Kyoto Stock Center) and the Bloomington Drosophila Stock Center. Genetic information was accessed via FlyBase, supported by grants from the National Human Genome Research Institute (U24 HG013300) and the Wellcome Trust.

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