Gooseberry (gene)

''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. The gene also has clinical significance, being linked to diseases such as Waardenburg Syndrome and rhabdomyosarcoma.

Discovery

The ''gooseberry'' gene was first described in a 1980 research paper on ''Drosophila'' embryonic development. 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 categories: segment-polarity, pair-rule, and gap. ''Gooseberry'', a member of these 15 genes, was classified as a segment-polarity gene.

Gene expression

''Drosophila'' embryos show developmental stage-dependent expression of ''gsb.'' 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.
The ''gsb'' expression profile of adult ''Drosophila'' shows the 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.

Structure

Gooseberry contains an N-terminal PAX ( paired box) and C-terminal homeobox domains.

Function

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

Wingless signaling

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.

Typical ''gooseberry'' expression in ''Drosophila'' embryos requires Wg activation. 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 (
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.

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''.

Waardenburg syndrome

Waardenburg Syndrome (WS) is an inherited condition known to cause deafeness and pigmentation irregularities. ''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. In ''Drosophila'', this region is classified as a DNA-binding site called a homeodomain. Considering this knowledge, it is believed that the mechanism underlying WS phenotypes involves altered DNA binding in ''PAX3'' variants. Elucidation of this link between ''PAX3'' and ''gooseberry'' have directed the molecular study of ''PAX3''-associated phenotypes including emphasis on DNA binding studies.

Rhabdomyosarcoma

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

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. Additionally, ''PAX7'' and ''gooseberry'' have been found to show similar segmented expression during neural development, suggesting links to rhabdomyosarcoma metastasis into the CNS.

References

{{Reflist

Wikipedia Student Program
Drosophila melanogaster genes
Hedgehog signaling pathway