Gooseberry (gene)

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

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 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]

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 (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 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]