HOX gene colinearity determines the body plan of an organism

<i>Hoxb-13</i>: a new Hox gene in a distant region of the HOXB cluster maintains colinearity. 1996. https://doi.org/10.1242/dev.122.8.2475

ABSTRACT The Hox genes are involved in patterning along the A/P axes of animals. The clustered organization of Hox genes is conserved from nematodes to vertebrates. During evolution, the number of Hox genes within the ancestral complex increased, exemplified by the five-fold amplification of the AbdB-related genes, leading to a total number of thirteen paralogs. This was followed by successive duplications of the cluster to give rise to the four vertebrate HOX clusters. A specific subset of paralogs was subsequently lost from each cluster, yet the composition of each cluster was likely conserved during tetrapod evolution. While the HOXA, HOXC and HOXD clusters contain four to five AbdB-related genes, only one gene (Hoxb-9) is found in the HOXB complex. We have identified a new member of paralog group 13 in human and mouse, and shown that it is in fact Hoxb-13. A combination of genetic and physical mapping demonstrates that the new gene is found approx. 70 kb upstream of Hoxb-9 in the same transcriptional orientation as the rest of the cluster. Despite its relatively large distance from the HOX complex, Hoxb-13 exhibits temporal and spatial colinearity in the main body axis of the mouse embryo. The onset of transcription occurs at E9.0 in the tailbud region. At later stages of development, Hoxb-13 is expressed in the tailbud and posterior domains in the spinal cord, digestive tract and urogenital system. However, it is not expressed in the secondary axes such as the limbs and genital tubercle. These results indicate that the 5′ end of the HOXB cluster has not been lost and that at least one member exists and is highly conserved among different vertebrate species. Because of its separation from the complex, Hoxb-13 may provide an important system to dissect the mechanism(s) responsible for the maintenance of colinearity.

Genomic Organization and Expression Demonstrate Spatial and Temporal Hox Gene Colinearity in the Lophotrochozoan Capitella sp. I. 2008. https://doi.org/10.1371/journal.pone.0004004

Hox genes define regional identities along the anterior–posterior axis in many animals. In a number of species, Hox genes are clustered in the genome, and the relative order of genes corresponds with position of expression in the body. Previous Hox gene studies in lophotrochozoans have reported expression for only a subset of the Hox gene complement and/or lack detailed genomic organization information, limiting interpretations of spatial and temporal colinearity in this diverse animal clade. We studied expression and genomic organization of the single Hox gene complement in the segmented poly

A Hox-Spalt Morphogenetic Gene Regulatory Network Links Organ Shape to the Body Plan ​. 2026. https://doi.org/10.2139/ssrn.6690578

Locomotion is the most significant behavior that drives organismal design. However, the mechanisms that connect musculoskeletal morphology to diverse anatomical features along the body axis are poorly understood. Using Drosophilabody wall muscles as a model of position-dependent morphological diversification, we show the Hox transcription factor Ultrabithorax (Ubx) activates expression of the zinc-finger transcription factor Spalt major (Salm) to regulate muscle shape. Hox genes in the Antennapedia-complex (ANT-C) are expressed in the anterior of the embryo and Hox genes inthe Bithorax-complex (BX-C), including Ubx, are expressed in the posterior. Body wall muscle morphology abruptly changes at ANT-C/BX-C expression boundary in the mesoderm and shifting the ANT-C/BX-C boundary concomitantly shifted muscle morphology. We identified a salm embryonic enhancer that is regulated by Hox genes in the BX-C but not by Hox genes in the ANT-C. Salm in turn activates a cytoskeletal regulatory module that governs muscle shape but not muscle identity. A Hox-Salm morphogenetic gene regulatory network therefore links region-specific muscle morphology to the body plan, providing a mechanism to couple locomotion and organismal design.

Rescue of Drosophila labial null mutant by the chicken ortholog Hoxb-1 demonstrates that the function of Hox genes is phylogenetically conserved.. 1996. https://doi.org/10.1101/gad.10.2.176

Hox complexes are important players in the establishment of the body plan of invertebrates and vertebrates. Sequence comparison demonstrates a remarkable phylogenetic conservation of key structural features of Hox genes. The correlation between the physical order of genes along the chromosomes and their domains of function along the body axis is conserved between arthropods and vertebrates. Ectopic expression experiments suggest that the functions of homeo proteins also are conserved between invertebrates and vertebrates. However, it remains an open question whether vertebrate Hox genes expressed under the control of Drosophila regulatory sequences can substitute the function of Drosophila Hox genes. We have studied this issue with the Drosophila labial (lab) gene and its chicken ortholog gHoxb-1. We fused the entire protein-coding region of gHoxb-1 with previously identified regulatory sequences of lab. This approach places gHoxb-1 into the normal embryonic spatiotemporal context in which lab acts. Ten transgenic lines carrying gHoxb-1 were established and tested for their ability to rescue lab null mutant animals. Eight lines rescued with high efficiency, embryonic lethality, and abnormal head morphogenesis, two defects observed in lab null mutant embryos. The rescue with the gHoxb-1 minigene was close to the efficiency of that obtained with the Drosophila lab minigene. This indicates that gHoxb-1 protein can regulate lab target genes and thereby restore embryonic viability. This is striking, as Lab and gHoxb-1 proteins are divergent except for their homeo domains and a short stretch of amino acids amino-terminal to the homeo domain. Our findings demonstrate a functional conservation of the lab class homeo proteins between insects and vertebrates and support the view that function of Hox genes resides in relatively few conserved motifs and largely in the homeo domain.

Hox targets and cellular functions.. 2013. https://doi.org/10.1155/2013/738257

Hox genes are a group of genes that specify structures along the anteroposterior axis in bilaterians. Although in many cases they do so by modifying a homologous structure with a different (or no) Hox input, there are also examples of Hox genes constructing new organs with no homology in other regions of the body. Hox genes determine structures though the regulation of targets implementing cellular functions and by coordinating cell behavior. The genetic organization to construct or modify a certain organ involves both a genetic cascade through intermediate transcription factors and a direct regulation of targets carrying out cellular functions. In this review I discuss new data from genome-wide techniques, as well as previous genetic and developmental information, to describe some examples of Hox regulation of different cell functions. I also discuss the organization of genetic cascades leading to the development of new organs, mainly using Drosophila melanogaster as the model to analyze Hox function.

Colinearity and non-colinearity in the expression of Hox genes in developing chick skin. 2002. https://doi.org/10.1387/ijdb.11934149

Hox genes are usually expressed temporally and spatially in a colinear manner with respect to their positions in the Hox complex. We found that these characteristics apply to several Hox genes expressed in developing chick skin (Hoxb-4, Hoxa-7 and Hoxc-8), and we classed this group of genes as regionally restricted. To our surprise, we found that most of the Hox genes we examined are regionally unrestricted in their expression in the embryonic chick skin. This second group includes the Hoxd genes, Hoxd-4 to Hoxd-13, Hoxa-11 and Hoxc-6. Temporally, the expression of the regionally restricted genes can be observed by E5 within the epidermis, whereas the spatially unrestricted genes are not expressed in the epidermis until E6.25. Unexpectedly, we found that all the unrestricted genes are expressed concomitantly and therefore do not conform to temporal colinearity. Moreover, the dermal expression for both groups occurs later, but maintains the same anteroposterior patterning to that seen previously in the epidermis. During embryonic day 7-8, expression for all genes is up-regulated within the dense dermis whilst being reduced within the inter-bud regions. Later expression within the bud mesenchyme is down-regulated whilst high levels of transcriptional activity are detectable within the epidermal sheath of each feather bud. These results indicate that the transcriptional activity of Hox genes in the developing chick skin could be important during embryonic skin patterning both by providing regionally restricted positional cues, and also by imparting generic signals necessary for feather morphology.

PubMed: [Homeotic genes].. https://pubmed.ncbi.nlm.nih.gov/1976313/

The high degree of phylogenetic conservation of the homeobox has made possible the identification and the isolation of more than fifty homeobox genes (Hox genes) in many eukaryotic organisms including nematode, Xenopus, mouse and man. In the mouse and human genomes Hox genes are clustered in tandem in four large gene complexes located on separate chromosomes. The relative positions of the genes within the clusters and the positions of the anterior boundaries of their expression domains along the anterior-posterior axis of the central nervous system and prevertebral column of the mouse embryo were found to be colinear. The similarities between the structure, organization and pattern of expression of the homeotic genes of Drosophila and of the homeobox genes of vertebrates suggest that some basic principles of embryonic organization and development have been preserved during the long period of evolution that has elapsed since the divergence of the phylogenetic lineages leading to vertebrates and arthropods. Published in Reproduction, nutrition, development (1990)

PubMed: Murine genes related to the Drosophila AbdB homeotic genes are sequentially expressed during development of the posterior part of the body.. https://pubmed.ncbi.nlm.nih.gov/1676674/

Murine genes related to the Drosophila AbdB homeotic genes are sequentially expressed during development of the posterior part of the body. The cloning, characterization and developmental expression patterns of two novel murine Hox genes, Hox-4.6 and Hox-4.7, are reported. Structural data allow us to classify the four Hox-4 genes located in the most upstream (5') position in the HOX-4 complex as members of a large family of homeogenes related to the Drosophila homeotic gene Abdominal B (AbdB). It therefore appears that these vertebrate genes are derived from a selective amplification of an ancestral gene which gave rise, during evolution, to the most posterior of the insect homeotic genes so far described. In agreement with the structural colinearity, these genes have very posteriorly restricted expression profiles. In addition, their developmental expression is temporally regulated according to a cranio-caudal sequence which parallels the physical ordering of these genes along the chromosome. We discuss the phylogenetic alternative in the evolution of genetic complexity by amplifying either genes or regulatory sequences, as exemplified by this system in the mouse and Drosophila.

Hox gene. https://en.wikipedia.org/wiki/Hox_gene

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 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 (for example, legs, ant Hox… Drosophila melanogaster is an important model organism for understanding body plan generation and evolution. The general principles of Hox gene function and logic elucidated in flies will apply to all bilaterian organisms, including humans. Drosophila, like all insects, has eight Hox genes. These are clustered into two complexes, both of which are located on chromosome 3. The Antennapedia complex (not to be confused with the Antp gene) consists of five genes: labial (lab), proboscipedia (pb), deformed (Dfd), sex combs reduced (Scr), and Antennapedia (Antp). The Bithorax complex, named after the Ultrabithorax gene, consists of the remaining three genes: Ultrabithorax (Ubx), abdominal-A (abd-A) and abdominal-B (abd-B). In…

Homeobox. https://en.wikipedia.org/wiki/Homeobox

silence the Hox genes by modulation of chromatin structure. Mutations to homeobox genes can produce easily visible phenotypic changes in body segment 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. Homeoboxes are found within genes that are involved in the regulation of patterns of anatomical development (morphogenesis) in animals, fungi, plants, an Hox genes are the most commonly known subset of homeobox genes. They are essential metazoan genes that determine the identity of embryonic regions along the anterior-posterior axis. The first vertebrate Hox gene was isolated in Xenopus by Edward De Robertis and colleagues in 1984. The main interest in this set of genes stems from their unique behavior and arrangement in the genome. Hox genes are typically found in an organized cluster. The linear order of Hox genes within a cluster is directly correlated to the order in which they are expressed in both time and space during development. This phenomenon is called colinearity. Mutations in these homeotic genes cause displacement of body segments during embryonic development. This is called ectopia. For example, when one gene is lost the segment develops into a more anterior one, while a mutation that leads to a gain of function causes a segment to develop into a more posterior one. Famous examples are Antennapedia and bithorax in Drosophila, which can cause the development of legs instead of antennae and the development of a duplicated thorax, respectively. In vertebrates, the four paralog clusters are partially redundant in function, but have also acquired several derived functions. For example, HoxA and HoxD specify segment identity along the limb axis. Specific members of the Hox family have been implicated in vascular remodeling, angiogenesis, and disease by orchestrating changes in matrix…

Hox genes and the evolution of the arthropod body plan.. 2002. https://doi.org/10.1046/j.1525-142x.2002.02034.x

In recent years researchers have analyzed the expression patterns of the Hox genes in a multitude of arthropod species, with the hope of understanding the mechanisms at work in the evolution of the arthropod body plan. Now, with Hox expression data representing all four major groups of arthropods (chelicerates, myriapods, crustaceans, and insects), it seems appropriate to summarize the results and take stock of what has been learned. In this review we summarize the expression and functional data regarding the 10 arthropod Hox genes: labial proboscipedia, Hox3/zen, Deformed, Sex combs reduced, fushi tarazu, Antennapedia, Ultrabithorax, abdominal-A, and Abdominal-B. In addition, we discuss mechanisms of developmental evolutionary change thought to be important for the emergence of novel morphological features within the arthropods.

Ancient origin of the Hox gene cluster.. 2001. https://doi.org/10.1038/35047605

The Hox gene cluster has a crucial function in body patterning during animal development. How and when this gene cluster originated is being clarified by recent data from Cnidaria, a basal animal phylum. The characterization of Hox-like genes from Hydra, sea anemones and jellyfish has revealed that a Hox gene cluster is extremely ancient, having originated even before the divergence of these basal animals.

Hox genes are not always Colinear.. 2006. https://doi.org/10.7150/ijbs.2.95

The deuterostomes are the clade of animals for which we have the most detailed understanding of Hox cluster organisation. With the Hox cluster of amphioxus (Branchiostoma floridae) we have the best prototypical, least derived Hox cluster for the group, whilst the urochordates present us with some of the most highly derived and disintegrated clusters. Combined with the detailed mechanistic understanding of vertebrate Hox regulation, the deuterostomes provide much of the most useful data for understanding Hox cluster evolution. Considering both the prototypical and derived deuterostome Hox clusters leads us to hypothesize that Temporal Colinearity is the main constraining force on Hox cluster organisation, but until we have a much deeper understanding of the mechanistic basis for this phenomenon, and know how widespread across the Bilateria the mechanism(s) is/are, then we cannot know how the Hox cluster of the last common bilaterian operated and what have been the major evolutionary forces operating upon the Hox gene cluster.

HOXA13 in etiology and oncogenic potential of Barrett’s esophagus. 2021. https://doi.org/10.1038/s41467-021-23641-8

Barrett's esophagus in gastrointestinal reflux patients constitutes a columnar epithelium with distal characteristics, prone to progress to esophageal adenocarcinoma. HOX genes are known mediators of position-dependent morphology. Here we show HOX collinearity in the adult gut while Barrett's esophagus shows high HOXA13 expression in stem cells and their progeny. HOXA13 overexpression appears sufficient to explain both the phenotype (through downregulation of the epidermal differentiation complex) and the oncogenic potential of Barrett's esophagus. Intriguingly, employing a mouse model that contains a reporter coupled to the HOXA13 promotor we identify single HOXA13-positive cells distally from the physiological esophagus, which is mirrored in human physiology, but increased in Barrett's esophagus. Additionally, we observe that HOXA13 expression confers a competitive advantage to cells. We thus propose that Barrett's esophagus and associated esophageal adenocarcinoma is the consequence of expansion of this gastro-esophageal HOXA13-expressing compartment following epithelial injury.