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Hox Gene Presented by: Asmaa Hassan Azza Elshafie Amna A/bagi Introduction and Discovery • How the undifferentiated cells in a fertilized embryo separate into a head and a tail end, and how the eyes, legs, antennae, and other organs all form in their correct positions? • which genes? • How many are they? • How do they work? • How the genes causing them cooperate during body segmentation? Ed Lewis, discoverer of homeotic genes and founder of developmental genetics Homeotic genes (Selector genes) Genes that encode proteins that bind to specific sequences of DNA and thus influence the organism’s subsequent development. or Are genes that determine which parts of the body form what body parts. • Homeotic proteins can activate one gene but repress another producing effects that complementary and necessary for the ordered development of an organisms. Homeotic genes specify body segment identity in Drosophila. Fig. 14 The bithorax pseudo-alleles normal wing T2 T3 post-bithorax haltere normal haltere one gene, or several genes??? The homeotic genes ANT-C and BX-C encode products are involved in controlling the normal development of the relevant adult fly structures. The Nobel Prize in Physiology or Medicine 1995 Edward B. Lewis Christiane -Volhard and Eric Wieschaus In 1983, he succeeded in cloning Antennapedia, one of the homeotic genes,which determines the characteristics of the body segments of Drosophila, and elucidated its structure. Furthermore, in the Walter Jakob Gehring Switzerland / March 20, 1939 Developmental Biologist; Professor, University of Basel Antennapedia gene, he found a specific base sequence common to all homeotic genes and called it "homeobox." Walter Gehring cloned Antennapedia (here, with Ed Lewis) and searched for homologies with the genes of the bithorax complex • A homeobox is a conserved* DNA sequence found within genes that are involved in the regulation of patterns of development (morphogenesis) in animals, fungi and plants. • Bind to another gene in turn, thus triggering a cascade of gene expressions resulting in the segmentation of the embryo. *Whether from flies, worms, mice, or humans, all homeotic genes contain a segment called a homeobox, made up of 180 base pairs of DNA, which codes for an important domain of a transcription factorÑa protein that regulates the activity of other genes. A homeobox is about 180 base pair long. It encodes protein domain (the homeodomain) 60 aa-long homeodomain which when expressed (e.g. as protein) can bind DNA. The homeodomain bound to DNA Function: Homeobox genes encode transcription factors which typically switch on cascades of other genes. • Recognize its desired target genes*. • Act in the promoter region of their target genes* as complexes with other transcription factors, often also homeodomain proteins. * The target genes of Hox genes promote cell division, cell adhesion, apoptosis, and cell migration. • Control genes are important elements in building complicated organisms like flies. • Help lay out the basic body forms of many animals, including humans, flies, and worms. They set up the head-to-tail organization “directing instructions “ Function of the Hox genes in vertebrates? CLASSIFICATION Homeotic Loci • HL = Genes whose products provide positional information in a multicellular embryo. • HOM-generally invertebrates • HOX-vertebrates • MADS-plants • Classification of homeobox genes into the following classes: • Hlx, NK-2, TCL, NEC, ems, Dll, msh, NK-1, en, Abd-b, Antp, lab, cad, eve, prd, prd-like, cut, POU, LIM, ZF. In Drosophila • In Drosophila hox cluster consists of eight genes arranged in two groups referred as Antennapedia complex and Bithorax complex on third chromosome named HOM-C (homeotic complex). Bithorax complex AbdominalA(abd-A) ultrabithorax(U bx) Antennapedia complex sex combs reduced(scr) deformed(dfd), Proboscipedia(p b), AbdominalB(Abd-B) Labial(lab), Antennapedia(a ntp) . Eight Genes Regulate the Identity of Within the Adult and Embryo labial (lab) proboscipedia (pb) Deformed (Dfd) Sex combs reduced (Scr) Antennapedia (Antp) Ultrabithorax (Ubx) abdominal A (abd-A) Abdominal B (Abd-B) . In human • Human HOX Genes (HOX clusters) • 39 Hox genes (i.e., they must be important) distributed in 4 linkage groups • Contain homeobox domain (highly conserved) • Genes are expressed in sequences that correlate with development of specific regions • ParaHox paralogon (4q, 5q, 13q and Xq) The NKL (NK-Like or NK-Linked) genes or MetaHox paralogon (2p/8p, 4p, 5q and 10q) Somewhat aberrantly, the Dlx and En gene families group with the NKL subclass in phylogenetic analyses. Chromosomal distribution of human homeobox genes Holland et al. BMC Biology 2007 Charactistics • Hox genes exhibit some important properties like; 1) Found in clusters: Hox genes are physically linked on the chromosome.Eight genes are organized in one cluster in flies (Drosophila) and four clusters harboring 39 hox genes in Humans. 2) Colinearity: The gene order in the cluster mimics the order of expression of genes and their function along the anterior–posterior (A–P) body axis: genes at the 5′ end of the cluster are expressed in, and pattern, the posterior part of the body, whereas genes at the 3′ end pattern the anterior end of the body. Colinearity They display colinearity: a) Spatial colinearity: the more anteriorly expressed genes are in one end(at the 3′ end ), the more posterior ones at the other end of the gene complex (at the 5′ end of the cluster). b)Temporal colinearity: genes on one end of the complex (anterior) are expressed first, those on the other (posterior) end are turned on last (In some species mainly vertebrates ). 3) Homeotic transformations: When mutant one segment gets transformed into likeness of another. For example Ultrabithorax (ubx) which is normally expresses in T3 segment of Drosophila ,plays a vital role is formation of Haltere (modified wing) by repressing various wing patterning genes. In flies mutant for ubx halteres are modified into wings and you have a four winged fruit fly. Developmental function of Ultrabithorax - in T3: reduce wings to halteres? 4) Functional hierarchies among genes in the cluster, called “phenotypic suppression” in Drosophila and “posterior prevalence” in vertebrates. Normally genes present in posterior region are dominant over anterior expressing ones. (Abdominal B in drosophila) is dominant over all others in complex). • When cells mutant for particular hox gene ,then the hox gene anterior to the mutant one will now starts expressing in those cells. Regulation Hierarchy of genes in Drosophila development Maternal factor Gap genes Development of the number of segments Pair rule genes Selector genes (Hox genes) Realisator genes Development of the features of the segments Before • The initial genes critical to this process are often collectively referred to as “maternal effect” genes based on the fact that they are transcriptionally derived from the maternal genome. • Of this group, the genes bicoid and nanos play critical roles in creating the initial polarity along the AP axis. • The designation of “anterior” is driven by the activities of Bicoid, where as posterior” specification relies on the activity of Nanos. • Bicoid and Nanos proteins regulate the activity of other maternal genes, including hunchback and caudal, respectively. • The interactions among these maternal factors ultimately create gradients within the embryo that will drive gene expression patterns during later stages of development. • Protein gradiants as follow: 1. From anterior posterior Bicoid and hunchback 2. From posterior anterior Nanos and caudal • Maternal factors stimulation of expression of gap genes(Kruppel, knirps ,giant, huckebein, tailless, orthodenticle, and button head) in overlapping domains along the AP axis. • As transcription factors, the products of these genes in turn regulate the expression of the pair-rule genes, which have expression domains that reveal a parasegmental organization within the embryo. Hierarchy of genes in Drosophila development giant (gap gene) hunchback (gap gene) bicoid (maternal factor) Krüppel (gap gene) Regulation • Gap and pair-rule proteins act through cis-acting regulatory regions referred to as initiator enhancer elements, to either activate or repress homeotic gene expression. • For example hunchback and Kruppel negatively regulate the homeotic genes Target The hox genes regulate what are called realisator genes or effectors genes that act : • at the bottom of such hierarchies to ultimately form the tissues, structures, and organs of each segment. • Segmentation involves such processes as morphogenesis (differentiation of precursor cells into their terminal specialized cells). • programmed cell death. • the movement of cells from where they are first born to where they will ultimately function. • it is not surprising that the target genes of Hox genes promote cell division, cell adhesion, apoptosis, and cell migration. After • In general, homeotic genes and their counterparts in other species require the activity of cofactor proteins to modulate their activity in a context-dependent manner • For example, one known target of homeotic selector proteins is the transcription factor Distal-less (Dll). • Dll is required for the formation of legs in thoracic segments, and its expression is negatively regulated in abdominal segments by the actions of Ubx and AbdA they bind to the enhancer and suppress it. • Another two cofactors Extradenticle (Exd) and Homothorax which act to improve the selectivity of DNA binding. • Exd binds different Hox proteins forming different heterodimers that bind selectively to specific target sequences • Exd may also contribute to specificity of Hox function by converting bound Hox proteins from repressors to activators. • The segmentation genes Sloppy-paired and Engrailed also contribute to the contextual activity of homeotic selector proteins These two cofactors do not influence DNA binding, but they appear to play a role in mediating the transcriptional repression by the homeotic selector proteins at the Dll repressor element. • One target gene is decapentaplegic (dpp), which is expressed in an A–P domain of VISCERAL MESO DERM in D melanogaster. • This dpp expression pattern is provided, in part, by the Hox proteins Ultrabithorax (UBX) and Abdominal-A (ABD-A), which activate and repress dpp transcription, respectively. Fixation • How, then, do fly embryonic cells “fix” the state of homeotic gene expression to ensure continuity during later stages? • The modification of chromatin structure appears to play a key role in the maintenance of homeotic selector gene expression. • Two classes of genes—the Polycomb Group and the Trithorax Group—play opposing roles with regard to stabilizing homeotic gene expression. • By remodeling chromatin structure into more compact states, the proteins of the Polycomb Group inactivate the cisregulatory regions that control homeotic genes, thereby inhibiting their transcription during subsequent stages • By contrast, the Trithorax Group proteins appear to act collectively to keep chromatin in a state that favors transcriptional activation Pattern of Binding of Polycomb Protein The normal pattern of binding of Polycomb protein to Drosophila giant chromosomes, visualized with an antibody against Polycomb. The protein is bound to the Antennapedia complex (ANT-C) and the bithorax complex (BX-C) as well as about 60 other sites. (A, from G. Struhl, Nature 293:36-41, 1981. ©1981 Macmillan Journals Ltd.; B, courtesy of B. Zink and R. Paro, from R. Paro, Trends Genet. 6:416-421, 1990.) Regulation in gene expression Evolution Evolution • Gene duplication is believed to play a major role in evolution. • The two genes that exist after a gene duplication event are: Paralogs (code for proteins with a different function and/or structure). Orthologous (code for proteins with similar functions but exist in different species) Susumu Ohno, 1970 HOX genes are evolutionarily highly conserved and control similar phenotypic characters among Distantly related organisms. Relatively closely related species. The formation of similar phenotypic characters can be explained by the conservation of shared hox genes. By contrast, different phenotypic characters are believed to be generated by duplication of hox genes and their functional differentiation. It has also been hypothesized that the loss of some hox genes are responsible for morphological differentiation. Short indels Duplications occur at all genomic scales! Domain (exon) Gene Gene cluster Segment Chromosome Genome Homeobox genes are present in the genomes of all animals which have so far been mapped as well as in the genomes of plants and fungi, indicating that the origins are ancient and precede the divergence of these kingdoms. The changes in Hox gene number and genomic organization played an important role in metazoan body-plan evolution Evolution of Hox gene cluster Hypothetical common ancestor Amphioxus Evolution of Hox gene cluster • Vertebrata genome contains 4 Hox clusters, Drosophyla genome contains only one. • In general: we can see one-to-four relationship between invertebrate and vertebrate gene number. • Two genome duplications happened. The Cambrian explosion • Nearly all the extant phyla of kingdom Animalia emerged within few tens of million years • This evolutionary explosion started about 530 million years ago • The assumed cause of it the genome duplication The genome duplications Larger Hox gene number More complicated body pattern Mutations Background • Among the most fascinating kinds of abnormalities in animals are those in which one normal body part is replaced by another (Homeosis). • Calvin Bridges (1915) isolated a spontaneous mutant of Drosophila in which part of the haltere was transformed into wing tissue. The mutant was called bithorax (duplication of a thoracic segment). • In the following decades other mutations affecting segment identity were identified e.g. certain Antennapedia mutations causing transformation of antennae into legs. Homeotic Mutations • The direction of homeotic transformations depends on whether the mutation causes Loss of homeotic gene function where the gene normally acts or Gain of function where the gene normally does not act. • Ultrabithorax (Ubx) acts in the haltere to promote haltere development and repress wing development. Loss of function mutations in Ubx transform the haltere into a wing. • In antenna-to-leg transformations of Antennapedia the mutants reflect a dominant gain of Antennapedia gene function in the antennae. Examples of Homeotic Mutations Normal adult fly Antennapedia mutant Bithorax mutant Antennapedia Mutations Wild-type Mutants Mammalian Hox mutation HOX genes play a fundamental role in the development of the vertebrate central nervous system, axial skeleton, limbs, gut, urogenital tract and external genitalia Hox Gene Expression in the Mammalian Limb HoxD gene complex is expressed in a specific pattern in the developing mouse forelimb. The pattern of gene expression correlates with the linear arrangement of the genes in the genome. Hox Gene Knockouts in Mice Lead to Limb Defects • Hoxa11 or Hoxd11 lead to the loss of the radius and ulna Cell Death & Digit Formation Some humans are born with webbed fingers Webs removed just after birth In normal development: Cell Death (Apoptosis) Occurs between Digits Large amount of lysosomal enzyme activity Syndactyly Hand foot genital syndrome HOXA13 mutation • There are several human syndromes which involve defects of the limbs and the Müllerian ducts or its derivatives. The hand-foot-genital (HFG) syndrome is an autosomal dominant (fully penetrant). • HOXA13 nonsense mutation (tryptophan → stop codon) . HOX GENES AND LUNG DEVELOPMENT Abnormal expression of HOX genes is associated with several congenital lung abnormalities e.g. HOXB5 is over-expressed in both Bronchopulmonary sequestration Congenital cystic adenomatoid malformation. HOX GENES AND LEUKAEMIA In leukaemia there is chromosomal translocations. Such translocations lead to the creation of fusion genes, and may involve individual HOX genes or regulators of HOX gene activity (HOXA9 or HOXD13 genes). HOX GENES AND CANCER Neoplastic growth in mammary epithelial cells is associated with increased expression of human growth hormone resulting in overexpression of HOXA1 in mammary carcinoma cells resulted in upregulation of Bcl-2, an antiapoptotic factor, and increased total cell numbers. Retinoic acid • RA probably plays a role in axis specification during normal development & appears to be critical for the initiation of limb bud outgrowth, also has been shown to activate the expression of more posterior Hox genes. • RA teratogenesis, in which mouse embryos exposed to retinoic acid show a different pattern of Hox gene expression along the anterior-posterior axis and abnormal differentiation of their axial structures. • Exogenous RA given to mouse embryos in utero can cause certain Hox genes to become expressed in groups of cells that usually do not express them.