Biology:Gooseberry (gene)

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Gooseberry
Gooseberry Protein 3D Structure.png
Gooseberry Protein 3D Structure[1]
Identifiers
OrganismDrosophila melanogaster
Symbolgsb
Alt. symbolsgsb-d, gooseberry-distal
Entrez38005
HomoloGene137820
RefSeq (mRNA)NM_079139.4
RefSeq (Prot)NP_523863.1
UniProtP09082
Other data
Chromosome2R: 25.06 - 25.07 Mb

Gooseberry (gsb) is a segment polarity gene located on chromosome 2 of the Drosophila (fruit fly) genome. Gooseberry is known for its interactions with key embryonic signaling pathways Wingless and Hedgehog.[2][3] The gene also has clinal significance, being linked to diseases such as Waardenburg Syndrome and rhabdomyosarcoma.[4][5][6][7]

Discovery

The gooseberry gene was first described in a 1980 research paper on Drosophila embryonic development.[2] In the study, Drosophila larvae were mutated at different genomic locations to identify genes affecting Drosophila embryonic segmental patterning. 15 candidate genes were found to affect this developmental process, and were subsequently classified into 3 different classes: segment-polarity, pair-rule, and gap. Gooseberry, a member of these 15 genes, was classified as a segment-polarity gene.[2][8]

Gene expression

gsb gene embryonic expression images[9]

Drosophila embryos show developmental stage-dependent expression of gsb.[9] This was determined by in situ hybridization gsb mRNA with a purple probe, allowing visualization of the gene expression.

  • Stages 1-3 exhibit no staining of gsb
  • Stages 4-6 display segmentally repeated expression in various ectodermal (outermost layer of the embryo) regions.
  • Stages 7-16 show independent and segmentally repeated expression in specific anatomical structures during different developmental stages. These structures include the ventral ectoderm, ventral epidermis, hypopharynx, and ventral nerve chord, which are all vital structures to embryonic development.
gsb gene expression profile in adult Drosophila - darker coloured boxes represent higher expression level. [10]

The gsb expression profile of adult Drosophila show highest accumulation in epithelial cells. This is expected, as segment polarity genes such as gsb are required for proper epidermal segment patterning, and the epithelium gives rise to the epidermis during fruit fly embryonic development.[11][12]

Structure

Gooseberry contains a N-terminal PAX (paired box) and C-terminal homeobox domains.[13]


Function

The Gooseberry protein interacts with critical development pathways in the fruit fly such as Wingless and Hedgehog.

Wingless signaling

Wnt Signalling pathway created using Biorender

The Drosophila cell fate determination pathway Wingless signaling (Wg), is activated by the signaling molecule Wnt, which inhibits the Wg destruction complex (WSDC). WSDC functions to break down β-catenin, a protein that binds to promoters of cell fate determination genes to promote expression.

In the absence of Wnt, Wg fails to activate, allowing WSDC to break down β-catenin, and preventing activation of genes.[14]

Typical gooseberry expression in Drosophila embryos requires Wg activation.[3] This implies that gooseberry is one of the cell fate determination genes promoted by β-catenin, and that its protein production is reliant on Wg for WSDC inhibition.

Hedgehog signaling

Hedgehog is a cell signalling pathway which directs cell development and tissue organization of developing Drosophila embryos.

During Drosophila central nervous system (CNS) development, Hedgehog and gooseberry assert differential regulatory effects on a key CNS development gene. This gene, huckebein (hkb), encodes a critical DNA-binding protein (Hkb) which influences developmental processes such as axon pathfinding and target recognition. Hedgehog activates hkb, while gooseberry represses hkb. Gooseberry achieves this by encoding a DNA-binding protein (a PAX-type transcription factor) which regulates gene activity and, in hkb's case, prevents activation.

The delicate interplay of positive signaling from Hedgehog and the repressive gooseberry helps establish a precise pattern of hkb expression in the developing fruit fly CNS, helping form complex neural structures.[15]

Clinical significance

Drosophila' s gooseberry gene has been used to study the vertebrate genes PAX3 and PAX7 in clinical settings. This is attributed to the gooseberry genes gsb-proximal and gsb-distal showing similar function to PAX3 and PAX7.[16][17][18]

Waardenburg syndrome

Waardenburg Syndrome (WS) is an inherited condition known to cause deafeness and pigmentation irregularities.[19] PAX3 variants are linked to type I & III WS, likely due to the gene's important role in the development of melanocytes. Studies have shown that many WS-causing PAX3 polymorphisms are found in a protein region that is conserved in the gsb protein.[20] In Drosophila, this region is classified as a DNA-binding site called a homeodomain.[21] Considering this knowledge, it is believed that the mechanism underlying WS phenotypes involves altered DNA binding in PAX3 variants.[22] Elucidation of this link between PAX3 and gooseberry have directed the molecular study of PAX3-associated phenotypes including emphasis on DNA binding studies.[21]

Rhabdomyosarcoma

Rhabdomyosarcoma is a rapidly progressing soft tissue cancer that disproportionately affects children.[7] PAX7 is a paired-box transcription factor involved in skeletal muscle formation/cellular role differentiation in mammals.[7][5] Increased PAX7 levels have been repeatedly implicated in cases of rhabdomyosarcoma, particularly embryonal rhabdomyosarcoma.[7][5][6]

Because of PAX7's homology with gooseberry, research has been able to exploit Drosophila models to study rhabdomyosarcoma. Transgenic fruit flies, whose genomes have been altered via genetic engineering, were studied and have implicated the known proliferation pathway Ras in the disease.[23][24] Additionally, PAX7 and gooseberry have been found to show similar segmented expression during neural development, suggesting links to rhabdomyosarcoma metastasis into the CNS.[25][26]

References

  1. ↑ "Protein gooseberry structure prediction". AlphaFold. https://alphafold.ebi.ac.uk/entry/P09082. 
  2. ↑ 2.0 2.1 2.2 "Mutations affecting segment number and polarity in Drosophila". Nature 287 (5785): 795–801. October 1980. doi:10.1038/287795a0. PMID 6776413. 
  3. ↑ 3.0 3.1 "Role of the gooseberry gene in Drosophila embryos: maintenance of wingless expression by a wingless--gooseberry autoregulatory loop". The EMBO Journal 12 (12): 4499–4509. December 1993. doi:10.1002/j.1460-2075.1993.tb06139.x. PMID 8223460. 
  4. ↑ "Mutations in the PAX3 gene causing Waardenburg syndrome type 1 and type 2". Nature Genetics 3 (1): 26–30. January 1993. doi:10.1038/ng0193-26. PMID 8490648. 
  5. ↑ 5.0 5.1 5.2 "RAGE signaling deficiency in rhabdomyosarcoma cells causes upregulation of PAX7 and uncontrolled proliferation". Journal of Cell Science 127 (Pt 8): 1699–1711. April 2014. doi:10.1242/jcs.136259. PMID 24554430. 
  6. ↑ 6.0 6.1 "PAX7 immunohistochemical evaluation of Ewing sarcoma and other small round cell tumours". Histopathology 73 (4): 645–652. October 2018. doi:10.1111/his.13689. PMID 29920735. 
  7. ↑ 7.0 7.1 7.2 7.3 "PAX7 Expression in Rhabdomyosarcoma, Related Soft Tissue Tumors, and Small Round Blue Cell Neoplasms" (in en-US). The American Journal of Surgical Pathology 40 (10): 1305–1315. October 2016. doi:10.1097/PAS.0000000000000717. PMID 27526298. 
  8. ↑ "The gooseberry-zipper region of Drosophila: five genes encode different spatially restricted transcripts in the embryo". The EMBO Journal 6 (9): 2793–2801. September 1987. doi:10.1002/j.1460-2075.1987.tb02575.x. PMID 16453795. 
  9. ↑ 9.0 9.1 "Gooseberry-Distal". Berkeley Drosophila Genome Project. https://insitu.fruitfly.org/cgi-bin/ex/report.pl?ftype=10&ftext=FBgn0001148. 
  10. ↑ "Dmel\gsb". FlyBase Gene Report. https://flybase.org/reports/FBgn0001148#expression. 
  11. ↑ "The role of segment polarity genes during Drosophila neurogenesis". Genes & Development 3 (6): 890–904. June 1989. doi:10.1101/gad.3.6.890. PMID 2501154. 
  12. ↑ "Genetic control of epidermis differentiation in Drosophila". The International Journal of Developmental Biology 48 (2-3): 207–215. 2004. doi:10.1387/ijdb.15272387. PMID 15272387. 
  13. ↑ "Protein gooseberry". InterPro. European Molecular Biology Laboratory (EMBL) - European Bioinformatics Institute (EBI). https://www.ebi.ac.uk/interpro/protein/UniProt/P09082/entry/pfam/#table. 
  14. ↑ "Wnt signaling networks in autism spectrum disorder and intellectual disability". Journal of Neurodevelopmental Disorders 8 (1): 45. 2016-12-05. doi:10.1186/s11689-016-9176-3. PMID 27980692. 
  15. ↑ "Establishing neuroblast-specific gene expression in the Drosophila CNS: huckebein is activated by Wingless and Hedgehog and repressed by Engrailed and Gooseberry". Development 124 (5): 1079–1087. March 1997. doi:10.1242/dev.124.5.1079. PMID 9056782. 
  16. ↑ "Synaptic homeostasis is consolidated by the cell fate gene gooseberry, a Drosophila pax3/7 homolog". The Journal of Neuroscience 30 (24): 8071–8082. June 2010. doi:10.1523/JNEUROSCI.5467-09.2010. PMID 20554858. 
  17. ↑ "Pax genes and their roles in cell differentiation and development". Current Opinion in Cell Biology 8 (6): 851–857. December 1996. doi:10.1016/S0955-0674(96)80087-1. PMID 8939674. 
  18. ↑ "Evolution and role of Pax genes". Current Opinion in Genetics & Development 3 (4): 595–605. August 1993. doi:10.1016/0959-437X(93)90095-7. PMID 8241771. 
  19. ↑ "Review and update of mutations causing Waardenburg syndrome". Human Mutation 31 (4): 391–406. April 2010. doi:10.1002/humu.21211. PMID 20127975. 
  20. ↑ "Phenotypic variation in Waardenburg syndrome: mutational heterogeneity, modifier genes or polygenic background?". Human Molecular Genetics 5 (4): 497–502. April 1996. PMID 8845842. https://academic.oup.com/hmg/article/5/4/497/595556. 
  21. ↑ 21.0 21.1 "Pax3 target gene recognition occurs through distinct modes that are differentially affected by disease-associated mutations". Pigment Cell Research 18 (6): 427–438. December 2005. doi:10.1111/j.1600-0749.2005.00275.x. PMID 16280008. 
  22. ↑ "Discordant phenotype of two overlapping deletions involving the PAX3 gene in chromosome 2q35". Human Molecular Genetics 2 (7): 953–959. July 1993. PMID 8103404. https://academic.oup.com/hmg/article/2/7/953/627285?login=true. 
  23. ↑ "A Drosophila model of the rhabdomyosarcoma initiator PAX7-FKHR". Proceedings of the National Academy of Sciences of the United States of America 103 (36): 13439–13444. September 2006. doi:10.1073/pnas.0605926103. PMID 16938866. 
  24. ↑ "Probing for a deeper understanding of rhabdomyosarcoma: insights from complementary model systems". Nature Reviews. Cancer 15 (7): 426–439. July 2015. doi:10.1038/nrc3961. PMID 26105539. 
  25. ↑ "The murine paired box gene, Pax7, is expressed specifically during the development of the nervous and muscular system". Mechanisms of Development 33 (1): 27–37. December 1990. doi:10.1016/0925-4773(90)90132-6. PMID 1982921. 
  26. ↑ "If rhabdomyosarcoma spreads" (in en). Jun 2021. https://cancer.ca/en/cancer-information/cancer-types/rhabdomyosarcoma/if-cancer-spreads. 



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