Gooseberry | |||||||
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Identifiers | |||||||
Organism | |||||||
Symbol | gsb | ||||||
Alt. symbols | gsb-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 | ||||||
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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]
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]
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.
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]
Gooseberry contains a N-terminal PAX (paired box) and C-terminal homeobox domains. [13]
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]
Sonic hedgehog protein (SHH) is encoded for by the SHH gene. The protein is named after the video game character Sonic the Hedgehog.
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.
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.
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.
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.
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.
The Hedgehog signaling pathway is a signaling pathway that transmits information to embryonic cells required for proper cell differentiation. Different parts of the embryo have different concentrations of hedgehog signaling proteins. The pathway also has roles in the adult. Diseases associated with the malfunction of this pathway include cancer.
Myogenesis is the formation of skeletal muscular tissue, particularly during embryonic development.
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.
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.
Alveolar rhabdomyosarcoma (ARMS) is a subtype of the rhabdomyosarcoma soft tissue cancer family whose lineage is from mesenchymal cells and are related to skeletal muscle cells. ARMS tumors resemble the alveolar tissue in the lungs. Tumor location varies from patient to patient, but is commonly found in the head and neck region, male and female urogenital tracts, the torso, and extremities. Two fusion proteins can be associated with ARMS, but are not necessary, PAX3-FKHR. and PAX7-FKHR. In children and adolescents ARMS accounts for about 1 percent of all malignancies, has an incidence rate of 1 per million, and most cases occur sporadically with no genetic predisposition. PAX3-FOXO1 is now known to drive cancer-promoting gene expression programs through creation of distant genetic elements called super enhancers.
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.
Paired-like homeodomain transcription factor 2 also known as pituitary homeobox 2 is a protein that in humans is encoded by the PITX2 gene.
Transcription factor SOX-10 is a protein that in humans is encoded by the SOX10 gene.
Indian hedgehog homolog (Drosophila), also known as IHH, is a protein which in humans is encoded by the IHH gene. This cell signaling protein is in the hedgehog signaling pathway. The several mammalian variants of the Drosophila hedgehog gene (which was the first named) have been named after the various species of hedgehog; the Indian hedgehog is honored by this one. The gene is not specific to Indian hedgehogs.
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.