Homeotic genes are genes which regulate the development of anatomical structures in various organisms such as echinoderms, [1] insects, mammals, and plants. Homeotic genes often encode transcription factor proteins, and these proteins affect development by regulating downstream gene networks involved in body patterning. [2]
Mutations in homeotic genes cause displaced body parts (homeosis), such as antennae growing at the posterior of the fly instead of at the head. [3] Mutations that lead to development of ectopic structures are usually lethal. [4]
There are several subsets of homeotic genes. They include many of the Hox and ParaHox genes that are important for segmentation. [5] Hox genes are found in bilateral animals, including Drosophila (in which they were first discovered) and humans. Hox genes are a subset of the homeobox genes. The Hox genes are often conserved across species, so some of the Hox genes of Drosophila are homologous to those in humans. In general, Hox genes play a role of regulating expression of genes as well as aiding in development and assignment of specific structures during embryonic growth. This can range from segmentation in Drosophila to central nervous system (CNS) development in vertebrates. [6] Both Hox and ParaHox are grouped as HOX-Like (HOXL) genes, a subset of the ANTP class (named after the Drosophila gene, Antennapedia). [7]
They also include the MADS-box-containing genes involved in the ABC model of flower development. [8] Besides flower-producing plants, the MADS-box motif is also present in other organisms such as insects, yeasts, and mammals. They have various functions depending on the organism including flower development, proto-oncogene transcription, and gene regulation in specific cells (such as muscle cells). [9]
Despite the terms being commonly interchanged, not all homeotic genes are Hox genes; the MADS-box genes are homeotic but not Hox genes. Thus, the Hox genes are a subset of homeotic genes.
One of the most commonly studied model organisms in regards to homeotic genes is the fruit fly Drosophila melanogaster . Its homeotic Hox genes occur in either the Antennapedia complex (ANT-C) or the Bithorax complex (BX-C) discovered by Edward B. Lewis. [10] Each of the complexes focuses on a different area of development. The antennapedia complex consists of five genes, including proboscipedia, and is involved in the development of the front of the embryo, forming the segments of the head and thorax. [11] The bithorax complex consists of three main genes and is involved in the development of the back of the embryo, namely the abdomen and the posterior segments of the thorax. [12]
During development (starting at the blastoderm stage of the embryo), these genes are constantly expressed to assign structures and roles to the different segments of the fly's body. [13] For Drosophila, these genes can be analyzed using the Flybase database.
Much research has been done on homeotic genes in different organisms, ranging from basic understanding of how the molecules work to mutations to how homeotic genes affect the human body. Changing the expression levels of homeotic genes can negatively impact the organism. For example, in one study, a pathogenic phytoplasma caused homeotic genes in a flowering plant to either be significantly upregulated or downregulated. This led to severe phenotypic changes including dwarfing, defects in the pistils, hypopigmentation, and the development of leaf-like structures on most floral organs. [14] In another study, it was found that the homeotic gene Cdx2 acts as a tumor suppressor. In normal expression levels, the gene prevents tumorgenesis and colorectal cancer when exposed to carcinogens; however, when Cdx2 was not well expressed, carcinogens caused tumor development. [15] These studies, along with many others, show the importance of homeotic genes even after development.
A homeobox is a DNA sequence, around 180 base pairs long, that regulates large-scale anatomical features in the early stages of embryonic development. Mutations in a homeobox may change large-scale anatomical features of the full-grown organism.
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.
In evolutionary developmental biology, homeosis is the transformation of one organ into another, arising from mutation in or misexpression of certain developmentally critical genes, specifically homeotic genes. In animals, these developmental genes specifically control the development of organs on their anteroposterior axis. In plants, however, the developmental genes affected by homeosis may control anything from the development of a stamen or petals to the development of chlorophyll. Homeosis may be caused by mutations in Hox genes, found in animals, or others such as the MADS-box family in plants. Homeosis is a characteristic that has helped insects become as successful and diverse as they are.
Hox genes, a subset of homeobox genes, are a group of related genes that specify regions of the body plan of an embryo along the head-tail axis of animals. Hox proteins encode and specify the characteristics of 'position', ensuring that the correct structures form in the correct places of the body. For example, Hox genes in insects specify which appendages form on a segment, and Hox genes in vertebrates specify the types and shape of vertebrae that will form. In segmented animals, Hox proteins thus confer segmental or positional identity, but do not form the actual segments themselves.
Antennapedia is a Hox gene first discovered in Drosophila which controls the formation of legs during development. Loss-of-function mutations in the regulatory region of this gene result in the development of the second leg pair into ectopic antennae. By contrast gain-of-function alleles convert antennae into ectopic legs.
Homeobox protein CDX-2 is a protein that in humans is encoded by the CDX2 gene. The CDX2 protein is a homeobox transcription factor expressed in the nuclei of intestinal epithelial cells, playing an essential role in the development and function of the digestive system. CDX2 is part of the ParaHox gene cluster, a group of three highly conserved developmental genes present in most vertebrate species. Together with CDX1 and CDX4, CDX2 is one of three caudal-related genes in the human genome.
Pre-B-cell leukemia transcription factor 1 is a protein that in humans is encoded by the PBX1 gene. The homologous protein in Drosophila is known as extradenticle, and causes changes in embryonic development.
Homeobox protein Hox-B6 is a protein that in humans is encoded by the HOXB6 gene.
Homeobox protein Hox-B5 is a protein that in humans is encoded by the HOXB5 gene.
Homeobox protein Hox-A13 is a protein that in humans is encoded by the HOXA13 gene.
Homeobox protein Hox-D11 is a protein that in humans is encoded by the HOXD11 gene.
The Bithorax complex (BX-C) is one of two Drosophila melanogaster homeotic gene complexes, located on the right arm of chromosome 3. It is responsible for the differentiation of the posterior two-thirds of the fly by the regulation of three genes within the complex: Ultrabithorax (Ubx), abdominal A (abd-A), and Abdominal B (Abd-B).
Homeotic selector genes confer segment identity in Drosophila. They encode homeodomain proteins which interact with Hox and other homeotic genes to initiate segment-specific gene regulation. Homeodomain proteins are transcription factors that share a DNA-binding domain called the homeodomain. Changes in the expression and function of homeotic genes are responsible for the changes in the morphology of the limbs of arthropods as well as in the axial skeletons of vertebrates. Mutations in homeotic selector genes do not lead to elimination of a segment or pattern, but instead cause the segment to develop incorrectly.
Zerknüllt is a gene in the Antennapedia complex of Drosophila and other insects, where it operates very differently from the canonical Hox genes in the same gene cluster. Comparison of Hox genes between species showed that the Zerknüllt gene evolved from one of the standard Hox genes in insects through accumulating many amino acid changes, changing expression pattern, losing ancestral function and gaining a new function.
Michael Levine is an American developmental and cell biologist at Princeton University, where he is the Director of the Lewis-Sigler Institute for Integrative Genomics and a Professor of Molecular Biology.
The Cdx gene family, also called caudal genes, are a group of genes found in many animal genomes. Cdx genes contain a homeobox DNA sequence and code for proteins that act as transcription factors. The gene after which the gene family is named is the caudal or cad gene of the fruitfly Drosophila melanogaster. The human genome has three Cdx genes, called CDX1, CDX2 and CDX4. The zebrafish has no cdx2 gene, but two copies of cdx1 and one copy of cdx4. The Cdx gene in the nematode Caenorhabditis elegans is called pal-1.
Hox genes play a massive role in some amphibians and reptiles in their ability to regenerate lost limbs, especially HoxA and HoxD genes.
Proboscipedia (pb) is a protein coding gene in Drosophila melanogaster.
Homeobox protein CDX-4 is a protein that in humans is encoded by the CDX4 gene. This gene is a member of the caudal-related homeobox transcription factor family that also includes CDX1 and CDX2.
Thomas Charles Kaufman is an American geneticist. He is known for his work on the zeste-white region of the Drosophila X chromosome. He is currently a Distinguished Professor of biology at Indiana University, where he conducts his current research on Homeotic Genes in evolution and development.
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