Gooseberry (gene)

Last updated
Gooseberry
Gooseberry Protein 3D Structure.png
Gooseberry Protein 3D Structure [1]
Identifiers
Organism Drosophila melanogaster
Symbolgsb
Alt. symbolsgsb-d, gooseberry-distal
Entrez 38005
HomoloGene 137820
RefSeq (mRNA) NM_079139.4
RefSeq (Prot) NP_523863.1
UniProt P09082
Other data
Chromosome 2R: 25.06 - 25.07 Mb
Search for
Structures Swiss-model
Domains InterPro

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]

Contents

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 Gsb embryonic expression images.png
gsb gene embryonic expression images

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

gsb gene expression profile in adult Drosophila - darker coloured boxes represent higher expression level. Gsb Expression Data.png
gsb gene expression profile in adult Drosophila - darker coloured boxes represent higher expression level.

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 Wnt Signaling Pathway Activation and Inhibition (2).png
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]

Related Research Articles

<span class="mw-page-title-main">Sonic hedgehog protein</span> Signaling molecule in animals

Sonic hedgehog protein (SHH) is encoded for by the SHH gene. The protein is named after the video game character Sonic the Hedgehog.

<i>Drosophila</i> embryogenesis Embryogenesis of the fruit fly Drosophila, a popular model system

Drosophila embryogenesis, the process by which Drosophila embryos form, is a favorite model system for genetics and developmental biology. The study of its embryogenesis unlocked the century-long puzzle of how development was controlled, creating the field of evolutionary developmental biology. The small size, short generation time, and large brood size make it ideal for genetic studies. Transparent embryos facilitate developmental studies. Drosophila melanogaster was introduced into the field of genetic experiments by Thomas Hunt Morgan in 1909.

<span class="mw-page-title-main">Morphogen</span> Biological substance that guides development by non-uniform distribution

A morphogen is a substance whose non-uniform distribution governs the pattern of tissue development in the process of morphogenesis or pattern formation, one of the core processes of developmental biology, establishing positions of the various specialized cell types within a tissue. More specifically, a morphogen is a signaling molecule that acts directly on cells to produce specific cellular responses depending on its local concentration.

<span class="mw-page-title-main">Neurula</span> Embryo at the early stage of development in which neurulation occurs

A neurula is a vertebrate embryo at the early stage of development in which neurulation occurs. The neurula stage is preceded by the gastrula stage; consequentially, neurulation is preceded by gastrulation. Neurulation marks the beginning of the process of organogenesis.

<span class="mw-page-title-main">Pax genes</span> Family of transcription factors

In evolutionary developmental biology, Paired box (Pax) genes are a family of genes coding for tissue specific transcription factors containing an N-terminal paired domain and usually a partial, or in the case of four family members, a complete homeodomain to the C-terminus. An octapeptide as well as a Pro-Ser-Thr-rich C terminus may also be present. Pax proteins are important in early animal development for the specification of specific tissues, as well as during epimorphic limb regeneration in animals capable of such.

<span class="mw-page-title-main">PAX3</span> Paired box gene 3

The PAX3 gene encodes a member of the paired box or PAX family of transcription factors. The PAX family consists of nine human (PAX1-PAX9) and nine mouse (Pax1-Pax9) members arranged into four subfamilies. Human PAX3 and mouse Pax3 are present in a subfamily along with the highly homologous human PAX7 and mouse Pax7 genes. The human PAX3 gene is located in the 2q36.1 chromosomal region, and contains 10 exons within a 100 kb region.

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<span class="mw-page-title-main">Myogenesis</span> Formation of muscular tissue, particularly during embryonic development

Myogenesis is the formation of skeletal muscular tissue, particularly during embryonic development.

<i>Krüppel</i>

Krüppel is a gap gene in Drosophila melanogaster, located on the 2R chromosome, which encodes a zinc finger C2H2 transcription factor. Gap genes work together to establish the anterior-posterior segment patterning of the insect through regulation of the transcription factor encoding pair rule genes. These genes in turn regulate segment polarity genes. Krüppel means "cripple" in German, named for the crippled appearance of mutant larvae, who have failed to develop proper thoracic and anterior segments in the abdominal region. Mutants can also have abdominal mirror duplications.

<span class="mw-page-title-main">Gap gene</span> Gene used to develop body sections in embryos

A gap gene is a type of gene involved in the development of the segmented embryos of some arthropods. Gap genes are defined by the effect of a mutation in that gene, which causes the loss of contiguous body segments, resembling a gap in the normal body plan. Each gap gene, therefore, is necessary for the development of a section of the organism.

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<span class="mw-page-title-main">Pair-rule gene</span> Gene involved in the development of segmented embryos of insects

A pair-rule gene is a type of gene involved in the development of the segmented embryos of insects. Pair-rule genes are expressed as a result of differing concentrations of gap gene proteins, which encode transcription factors controlling pair-rule gene expression. Pair-rule genes are defined by the effect of a mutation in that gene, which causes the loss of the normal developmental pattern in alternating segments.

<span class="mw-page-title-main">PITX2</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">SOX10</span> Transcription factor gene of the SOX family

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<span class="mw-page-title-main">Indian hedgehog (protein)</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">PAX7</span> Paired box transcription factor protein

Paired box protein Pax-7 is a protein that in humans is encoded by the PAX7 gene.

Patched (Ptc) is a conserved 12-pass transmembrane protein receptor that plays an obligate negative regulatory role in the Hedgehog signaling pathway in insects and vertebrates. Patched is an essential gene in embryogenesis for proper segmentation in the fly embryo, mutations in which may be embryonic lethal. Patched functions as the receptor for the Hedgehog protein and controls its spatial distribution, in part via endocytosis of bound Hedgehog protein, which is then targeted for lysosomal degradation.

A segmentation gene is a generic term for a gene whose function is to specify tissue pattern in each repeated unit of a segmented organism. Animals are constructed of segments; however, Drosophila segments also contain subdivided compartments. There are five gene classes which each contribute to the segmentation and development of the embryonic drosophila. These five gene classes include the coordinate gene, gap gene, pair-rule gene, segment polarity gene, and homeotic gene. In embryonic drosophila, the pair-rule gene defines odd-skipped and even-skipped genes as parasegments, showing 7 stripes in the embryo. In the next gene class, segment polarity gene, individual segments each have their own anterior and posterior pole, resulting in 14 segments. In the fruit fly Drosophila melanogaster, segment polarity genes help to define the anterior and posterior polarities within each embryonic parasegment by regulating the transmission of signals via the Wnt signaling pathway and Hedgehog signaling pathway. Segment polarity genes are expressed in the embryo following expression of the gap genes and pair-rule genes. The most commonly cited examples of these genes are engrailed and gooseberry in Drosophila melanogaster. The segment polarity is the last step in embryonic development and a repeated pattern where each half of each segment is deleted and a mirror-image is duplicated and reversed to replace that half segment; thus, forming a pattern element.

Dally is the name of a gene that encodes a HS-modified-protein found in the fruit fly. The protein has to be processed after being codified, and in its mature form it is composed by 626 amino acids, forming a proteoglycan rich in heparin sulfate which is anchored to the cell surface via covalent linkage to glycophosphatidylinositol (GPI), so we can define it as a glypican. For its normal biosynthesis it requires sugarless (sgl), a gene that encodes an enzyme which plays a critical role in the process of modification of dally.

References

  1. ↑ "Protein gooseberry structure prediction". AlphaFold– via EMBL-EBI.
  2. 1 2 3 Nüsslein-Volhard C, Wieschaus E (October 1980). "Mutations affecting segment number and polarity in Drosophila". Nature. 287 (5785): 795–801. Bibcode:1980Natur.287..795N. doi:10.1038/287795a0. PMID   6776413.
  3. 1 2 Li X, Noll M (December 1993). "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. doi:10.1002/j.1460-2075.1993.tb06139.x. PMC   413875 . PMID   8223460.
  4. ↑ Tassabehji M, Read AP, Newton VE, Patton M, Gruss P, Harris R, et al. (January 1993). "Mutations in the PAX3 gene causing Waardenburg syndrome type 1 and type 2". Nature Genetics. 3 (1): 26–30. doi:10.1038/ng0193-26. PMID   8490648.
  5. 1 2 3 Riuzzi F, Sorci G, Sagheddu R, Sidoni A, Alaggio R, Ninfo V, et al. (April 2014). "RAGE signaling deficiency in rhabdomyosarcoma cells causes upregulation of PAX7 and uncontrolled proliferation". Journal of Cell Science. 127 (Pt 8): 1699–1711. doi: 10.1242/jcs.136259 . PMID   24554430.
  6. 1 2 Toki S, Wakai S, Sekimizu M, Mori T, Ichikawa H, Kawai A, et al. (October 2018). "PAX7 immunohistochemical evaluation of Ewing sarcoma and other small round cell tumours". Histopathology. 73 (4): 645–652. doi:10.1111/his.13689. PMID   29920735.
  7. 1 2 3 4 Charville GW, Varma S, Forgó E, Dumont SN, Zambrano E, Trent JC, et al. (October 2016). "PAX7 Expression in Rhabdomyosarcoma, Related Soft Tissue Tumors, and Small Round Blue Cell Neoplasms". The American Journal of Surgical Pathology. 40 (10): 1305–1315. doi:10.1097/PAS.0000000000000717. PMID   27526298.
  8. ↑ Côté S, Preiss A, Haller J, Schuh R, Kienlin A, Seifert E, et al. (September 1987). "The gooseberry-zipper region of Drosophila: five genes encode different spatially restricted transcripts in the embryo". The EMBO Journal. 6 (9): 2793–2801. doi:10.1002/j.1460-2075.1987.tb02575.x. PMC   553705 . PMID   16453795.
  9. 1 2 "Gooseberry-Distal". Berkeley Drosophila Genome Project. Retrieved 2023-11-16.
  10. ↑ "Dmel\gsb". FlyBase Gene Report. Retrieved 23 October 2023.
  11. ↑ Patel NH, Schafer B, Goodman CS, Holmgren R (June 1989). "The role of segment polarity genes during Drosophila neurogenesis". Genes & Development. 3 (6): 890–904. doi: 10.1101/gad.3.6.890 . PMID   2501154.
  12. ↑ Payre F (2004). "Genetic control of epidermis differentiation in Drosophila". The International Journal of Developmental Biology. 48 (2–3): 207–215. doi: 10.1387/ijdb.15272387 . PMID   15272387.
  13. ↑ "Protein gooseberry". InterPro. European Molecular Biology Laboratory (EMBL) - European Bioinformatics Institute (EBI). P09082.
  14. ↑ Kwan V, Unda BK, Singh KK (2016-12-05). "Wnt signaling networks in autism spectrum disorder and intellectual disability". Journal of Neurodevelopmental Disorders. 8 (1): 45. doi: 10.1186/s11689-016-9176-3 . PMC   5137220 . PMID   27980692.
  15. ↑ McDonald JA, Doe CQ (March 1997). "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. doi:10.1242/dev.124.5.1079. PMID   9056782.
  16. ↑ Marie B, Pym E, Bergquist S, Davis GW (June 2010). "Synaptic homeostasis is consolidated by the cell fate gene gooseberry, a Drosophila pax3/7 homolog". The Journal of Neuroscience. 30 (24): 8071–8082. doi:10.1523/JNEUROSCI.5467-09.2010. PMC   3291498 . PMID   20554858.
  17. ↑ Mansouri A, Hallonet M, Gruss P (December 1996). "Pax genes and their roles in cell differentiation and development". Current Opinion in Cell Biology. 8 (6): 851–857. doi:10.1016/S0955-0674(96)80087-1. hdl: 11858/00-001M-0000-0013-00BE-3 . PMID   8939674.
  18. ↑ Noll M (August 1993). "Evolution and role of Pax genes". Current Opinion in Genetics & Development. 3 (4): 595–605. doi:10.1016/0959-437X(93)90095-7. PMID   8241771.
  19. ↑ Pingault V, Ente D, Dastot-Le Moal F, Goossens M, Marlin S, Bondurand N (April 2010). "Review and update of mutations causing Waardenburg syndrome". Human Mutation. 31 (4): 391–406. doi: 10.1002/humu.21211 . PMID   20127975.
  20. ↑ Pandya A, Xia XJ, Landa BL, Arnos KS, Israel J, Lloyd J, et al. (April 1996). "Phenotypic variation in Waardenburg syndrome: mutational heterogeneity, modifier genes or polygenic background?". Human Molecular Genetics. 5 (4): 497–502. doi:10.1093/hmg/5.4.497. PMID   8845842.
  21. 1 2 Corry GN, Underhill DA (December 2005). "Pax3 target gene recognition occurs through distinct modes that are differentially affected by disease-associated mutations". Pigment Cell Research. 18 (6): 427–438. doi:10.1111/j.1600-0749.2005.00275.x. PMID   16280008.
  22. ↑ Pasteris NG, Trask BJ, Sheldon S, Gorski JL (July 1993). "Discordant phenotype of two overlapping deletions involving the PAX3 gene in chromosome 2q35". Human Molecular Genetics. 2 (7): 953–959. doi:10.1093/hmg/2.7.953. PMID   8103404.
  23. ↑ Galindo RL, Allport JA, Olson EN (September 2006). "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. Bibcode:2006PNAS..10313439G. doi: 10.1073/pnas.0605926103 . PMC   1569182 . PMID   16938866.
  24. ↑ Kashi VP, Hatley ME, Galindo RL (July 2015). "Probing for a deeper understanding of rhabdomyosarcoma: insights from complementary model systems". Nature Reviews. Cancer. 15 (7): 426–439. doi:10.1038/nrc3961. PMC   4599785 . PMID   26105539.
  25. ↑ Jostes B, Walther C, Gruss P (December 1990). "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. doi:10.1016/0925-4773(90)90132-6. hdl: 11858/00-001M-0000-0013-0CE0-6 . PMID   1982921.
  26. ↑ "If rhabdomyosarcoma spreads". Canadian Cancer Society. Jun 2021. Retrieved 2023-11-21.
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