Hox Genes
Morphology, i.e., the shape of body structures and organs, are determined by a class of genes known in mammals as Hox genes (that is homologous to Homeotic genes in Drosophila melanogaster, or fruit fly). Hox genes are also termed selector genes or morphogens because they are responsible for cells' shape and for the tissue-specific specialized functions of cells, known as cell differentiation.
Although animal morphology varies among species, molecular biology has discovered in recent years that Hox genes are present in every animal species. Hox genes all contain a highly conserved nucleotide sequence called homeobox. Homeobox is a short stretch of about 180 nucleotides whose base sequence is very similar in all Hox genes (and Drosophila's homeotic genes). Apparently, homeoboxes regulate both timing and location of expression of particular groups of genes along a given embryonic axis during development.
A highly conserved structure or feature implies that, throughout the biological evolutionary process, such structures or functional features continue to be used in different species, after first appearing in a common ancestral one. For example, Hox genes are present in species as different as fruit flies (first termed homeotic genes), leeches, snails, fish, chickens, lions, and humans. Hox genes in every species are therefore homologous, which means that they have a similar function in different species; also that they derived through divergence from a primeval common ancestral gene that first appeared in a primitive animal about 1 billion years ago.
Hox genes are found in clusters in DNA, and are selector genes, because when activated in a given region of the embryo, the cells expressing them begin differentiating themselves, and grow into a specific direction, gradually organizing a specific structure or tissue, a process known as morphogenesis, or shape formation. Hox genes are crucial for embryo development, acting as regional guides to the morphogenetic development of limbs, heads, tails, fingers, hair, eyes, ears, scales, skin, and the internal organs, tissues and bones in every animal species. They also are instrumental in the maintenance of cell differentiation throughout the life of animal organisms, ensuring that replicating cells in a given tissue will produce daughter cells capable of the same tissue-specific functions. Loss of cell differentiation (anaplasia) occurs in many organs and tissues with aging, consequently leading to loss of tissue/organ function. Such a loss of differentiation is implied in many types of cancer as well, because it favors deregulated cell proliferation and tumor formation.
Hox (or homeotic) genes transcribe (i.e., produce) a class of proteins known as transcription factors that, in turn, promote the expression of other genes encoding the necessary proteins for a given structure to be developed, thus triggering cell differentiation. Through the controlled and selective expression of other genes, Hox genes therefore regulate embryo segments' development into fins, tails, heads, limbs, etc. They also control the sequence and timing of development in each segment, from back to front, from bottom to top, and from lower (or internal) to upper (or more external) layers of tissue.
The number of Hox genes increases (gene amplification) with the complexity of animal organisms. Therefore, more complex bodies have more Hox genes than the less complex ones. Such increase is achieved through gene duplications inside a single cluster and they are found greatly augmented in vertebrates by serial duplications of the whole ancestral clusters.
The order of expression of Hox genes in each cluster keeps a strict correspondence with their domains of expression in the embryonic body. This is known as rule of structural colinearity. This fact was first observed in 1985 in the fruit fly Drosophila melanogaster. Fruit flies have been studied as an important tool for the understanding of both gene and protein functions, being a very useful model organism due to a combination of its easily manipulated genetic system and a complex biology, comparable to that of mammals. Drosophila melanogaster have many genes with their correspondent highly conserved homologues in mammals, including humans. Therefore, it has been adopted as a model to Hox genes studies, along with mouse. Structural colinearity rule was also confirmed in 1988 in mouse, being later found in birds, nematodes, and leeches.
Structural colinearity rule determines that posterior domains of Hox genes' expression are dominant over more anterior ones. This implies that Hox genes expression starts from the posterior end. For example, in head-tail axis, tail Hox genes are dominant over head Hox genes, thus going into expression first.
Mutations in a given cluster of Hox genes in the embryo lead to malformation of the corresponding body structure, such as head or limbs, or fingers. When genes in a cluster undergo mutation, the wrong body part will develop. Hundreds of thousands of infants are born every year in the world with cleft palate and brain abnormalities caused by mutations in Hox genes. Excessively high amounts of an acid form of vitamin A, known as retinoid acid, may cause Hox gene malfunction, leading mainly to head and face malformation.
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