Dally (gene)

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Dally (division abnormally delayed) is the name of a gene that encodes a HS-modified-protein found in the fruit fly ( Drosophila melanogaster ). The protein has to be processed after being codified, and in its mature form it is composed by 626 amino acids, [1] 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. [2] 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.

Contents

Dally’s function

Dally acts as a coreceptor for Frizzled, the receptor of the Wnt Glypican.jpg
Dally acts as a coreceptor for Frizzled, the receptor of the Wnt

Dally works as a co-receptor of some secreted signaling molecules as fibroblast growth factor, vascular endothelial growth factor, hepatocyte growth factor and members of the Wnt signaling pathway, TGF-b and Hedgehog families. It is also necessary for the cell division patterning during the post-embryonic development of the nervous system.

It is a regulatory component of the Wg receptor and is part of a multiprotein complex together with Frizzled (Fz) transmembrane proteins. Therefore, it regulates two cell growth factors in Drosophila melanogaster, Wingless (Wg) and Decapentaplegic (Dpp). It must be said that in vertebrates the equivalent to Dpp are Bone Morphogenetic Proteins, and the mammalian equal to Wg might be integrin-beta 4. The first one (Wg) controls cell proliferation and differentiation during embryos development, specifically in epidermis, whereas the latter (Dpp) plays a role in the imaginal discs’ growth.

Dpp and Wg are mutually antagonistic in patterning genitalia. [3] Concretely, dally selectively regulates both Wg signalling in epidermis and Dpp in genitalia. This selectivity is supposed to be controlled by the type of Glycosaminoglycan GAG bonded to the dally protein, considering that there is a huge structural variety in GAGs.

Tissue malformations occur in various situations. As said in the introduction, the sgl enzyme is essential for a normal biosynthesis of dally. That is why the absence or malfunction of this enzyme doesn’t allow the correct Wg and Dpp signalling. Also the expression of mutated dally proteins alters Wnt signalling pathways, which leads to anomalies in Drosophila melanogaster’s eye, antennal, genital, wing and neural morphogenesis.

Dally's location in chromosome 3 Location dally.jpg
Dally's location in chromosome 3

Gene location

Dally's gene was located in the chromosome 3, concretely in the region 3L 8820605-8884292. [4]

Mutations and its effects

The mutation of Dally is a consequence of the P-element and the place where it is located. It is possible to differentiate between the mutants Dally-P1 and Dally-P2, depending on where the insertion of P-element is. It is known that Dally-P2 generates a bigger amount of defects. This mutated Dally disrupts the cell cycle progression, delaying the process during the G2-mitosis transition. As a matter of fact, mutations affecting Dally disrupt patterning of many tissues, for instance of the nervous system. [5] Dally mutants display cell cycle progression defects in specific sets of dividing cells. Those mutations are pleiotropic and can affect viability and produce morphological defects in several adult tissues, such as the eye, antenna, wing and genitalia.

Treatment

Once the mutation has been codified and the protein is functional, there is no chance to turn back and we will speak about a mutated individual. However, if the mutant dally is codified but it is not performing its function yet, a chaperone can identify it and try to correct the mutation, or directly send it to a proteasome using ubiquitins and degrade it.

Notwithstanding, there is another possible solution when malformations have occurred as a result of Wg activity loss. Ectopic dally can potentiate Wg signaling but this effect is dependent on some Wg activity remaining at the cell surface. Moreover, ectopic expression of dally+ from hs-dally+ transgene, stimulates Wg signaling. Thus, naked larval cuticle [6] loss is recuperated and once the larva has become an adult, its tissues execute their normal function. Despite this fact, an intense expression of dally+ results in the death of most of the Drosophila melanogaster’s embryos.

Related Research Articles

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The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved in animals, which means they are similar across animal species from fruit flies to humans.

<span class="mw-page-title-main">Chondrocyte</span> Cell that makes up cartilage

Chondrocytes are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans. Although the word chondroblast is commonly used to describe an immature chondrocyte, the term is imprecise, since the progenitor of chondrocytes can differentiate into various cell types, including osteoblasts.

<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.

Compartments can be simply defined as separate, different, adjacent cell populations, which upon juxtaposition, create a lineage boundary. This boundary prevents cell movement from cells from different lineages across this barrier, restricting them to their compartment. Subdivisions are established by morphogen gradients and maintained by local cell-cell interactions, providing functional units with domains of different regulatory genes, which give rise to distinct fates. Compartment boundaries are found across species. In the hindbrain of vertebrate embryos, rhobomeres are compartments of common lineage outlined by expression of Hox genes. In invertebrates, the wing imaginal disc of Drosophila provides an excellent model for the study of compartments. Although other tissues, such as the abdomen, and even other imaginal discs are compartmentalized, much of our understanding of key concepts and molecular mechanisms involved in compartment boundaries has been derived from experimentation in the wing disc of the fruit fly.

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<span class="mw-page-title-main">Ultrabithorax</span> Protein-coding gene found in Drosophila melanogaster

Ultrabithorax (Ubx) is a homeobox gene found in insects, and is used in the regulation of patterning in morphogenesis. There are many possible products of this gene, which function as transcription factors. Ubx is used in the specification of serially homologous structures, and is used at many levels of developmental hierarchies. In Drosophila melanogaster it is expressed in the third thoracic (T3) and first abdominal (A1) segments and represses wing formation. The Ubx gene regulates the decisions regarding the number of wings and legs the adult flies will have. The developmental role of the Ubx gene is determined by the splicing of its product, which takes place after translation of the gene. The specific splice factors of a particular cell allow the specific regulation of the developmental fate of that cell, by making different splice variants of transcription factors. In D. melanogaster, at least six different isoforms of Ubx exist.

<span class="mw-page-title-main">Mothers against decapentaplegic homolog 1</span> Protein-coding gene in the species Homo sapiens

Mothers against decapentaplegic homolog 1 also known as SMAD family member 1 or SMAD1 is a protein that in humans is encoded by the SMAD1 gene.

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<span class="mw-page-title-main">Frizzled</span> Family of G-protein coupled receptor proteins

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<span class="mw-page-title-main">Glypican</span>

Glypicans constitute one of the two major families of heparan sulfate proteoglycans, with the other major family being syndecans. Six glypicans have been identified in mammals, and are referred to as GPC1 through GPC6. In Drosophila two glypicans have been identified, and these are referred to as dally and dally-like. One glypican has been identified in C. elegans. Glypicans seem to play a vital role in developmental morphogenesis, and have been suggested as regulators for the Wnt and Hedgehog cell signaling pathways. They have additionally been suggested as regulators for fibroblast growth factor and bone morphogenic protein signaling.

<span class="mw-page-title-main">French flag model</span> Biological model

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<span class="mw-page-title-main">Cytoneme</span>

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Naked cuticle (Nkd) is a conserved family of intracellular proteins encoded in most animal genomes. The original mutants were discovered by 1995 Nobel laureates Christiane Nüsslein-Volhard and Eric F. Wieschaus and colleagues in their genetic screens for pattern-formation mutants in the fruit fly Drosophila melanogaster. The Nkd gene family was first cloned in the laboratory of Matthew P. Scott. Like many cleverly named fly mutants, the name "naked cuticle" derives from the fact that mutants lack most of the hair-like protrusions from their ventral cuticle and thus appear "naked".

Barry James Thompson is an Australian and British developmental biologist and cancer biologist. He is a professor of the John Curtin School of Medical Research at the Australian National University in Canberra. Thompson is known for identifying genes, proteins and mechanisms involved in epithelial polarity, morphogenesis and cell signaling via the Wnt and Hippo signaling pathways, which have key roles in human cancer.

Gary Struhl is an American research scientist whose primary areas of research are developmental biology and genetics and genomics. He works as a professor at Columbia University Medical Center, teaching neuroscience within the Department of Genetics and Development.

References

  1. Uniprot KB,
  2. Nakato H; Tracy A; Selleck SB (1995). "The division abnormally delayed (dally) gene: a putative integral membrane proteoglycan required for cell division patterning during postembryonic development of the nervous system in Drosophila". Development (121): 3687–3702.
  3. Emerald B.S.; Roy J. K. (1998). "Organising activities of engrailed, hedgehog, wingless and decapentaplegic in the genital discs of Drosophila melanogaster". Development Genes and Evolution. 208: 504–516. doi:10.1007/s004270050209.
  4. FlyBase,
  5. Varki A, Cummings R, Esko J, Freeze H, Stanley P, Bertozzi P, Hart G, Etzle M (2009). Essentials of Glycobiology, 2nd edition. ISBN   978-0-87969-770-9.
  6. Tsuda M, Kamimura K, Archer M, Fox B, Olson S (1999). "The cell-surface proteoglican Dally regulates Wingless signaling in Drosophila". Nature. 400 (6741): 276–280. doi:10.1038/22336. PMID   10421371.

Further reading