Special Issue "Hox Genes and Development"

A special issue of Journal of Developmental Biology (ISSN 2221-3759).

Deadline for manuscript submissions: closed (15 November 2015).

Special Issue Editor

Guest Editor
Prof. Dr. Vincenzo Zappavigna Website E-Mail
Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi 213/d, Modena 41125, Italy
Interests: Hox genes; TALE genes; transcriptional and post-transcriptional regulation; NUP98 oncoproteins; molecular biology of cancer; cell proliferation

Special Issue Information

Dear Colleagues,

Over three decades have passed since the seminal discovery that a restricted group of fruitfly genes controlling segment identity share a common sequence (the homeobox), which codes for an evolutionarily conserved and widespread DNA binding motif (the homeodomain). An utter breakthrough, which has opened up entirely new areas of investigation and revived "lagging" ones. Despite the passage of time, the field of Hox genes is far from looking "aged"; indeed, many aspects regarding Hox gene function are, to various extents, still obscure. How do Hox gene products gain their functional specificity in vivo? What are the genetic networks controlled by Hox proteins and how do they vary between different Hox proteins? What does it mean in molecular terms to specify a morphological trait? How do morphological changes in evolution relate to changes in Hox gene function? What is the biological significance of the evolutionary conservation of the collinear arrangement of Hox genes? What exactly is phenotypic suppression/posterior prevalence and what are the molecular mechanism(s) underlying it? What is the role played by Hox gene deregulation in human disease? These and many other questions in the "Hox field" are still awaiting definitive answers. This Special Issue of the Journal of Developmental Biology, while surely not having the ambition to provide conclusive answers to all the questions listed above, would like to represent an opportunity for "Hox people", old and new, to take stock of the situation of Hox gene research. Thus, all contributions regarding regulation and function at all levels, evo-devo, and role in disease of Hox genes are welcome. They can comprise new methods and approaches to study Hox gene function, including mathematical modelling, and reviews of what is known about how Hox proteins operate, how their expression is regulated, and on how Hox gene function goes awry in disease or disease models.

Dr. Vincenzo Zappavigna
Guest Editor

Manuscript Submission Information

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Keywords

  • embryonic axis patterning
  • transcriptional and post-transcriptional regulation in development
  • Hox transcription factors
  • TALE transcription factors
  • Evo-Devo
  • epigenetic control of gene expression
  • chromatin structure and gene expression
  • cell proliferation
  • cell differentiation

Published Papers (10 papers)

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Editorial

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Open AccessEditorial
Special Issue on HOX Genes in Development
J. Dev. Biol. 2017, 5(2), 5; https://doi.org/10.3390/jdb5020005 - 10 May 2017
Cited by 1
Abstract
This Special Issue of Journal of Developmental Biology (JDB) covers an indeed very “special” (at least to me) family of highly evolutionarily conserved genes, the Hox genes.[...] Full article
(This article belongs to the Special Issue Hox Genes and Development)

Research

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Open AccessArticle
Functional and Comparative Genomics of Hoxa2 Gene cis-Regulatory Elements: Evidence for Evolutionary Modification of Ancestral Core Element Activity
J. Dev. Biol. 2016, 4(2), 15; https://doi.org/10.3390/jdb4020015 - 26 Mar 2016
Abstract
Hoxa2 is an evolutionarily conserved developmental regulatory gene that functions to specify rhombomere (r) and pharyngeal arch (PA) identities throughout the Osteichthyes. Japanese medaka (Oryzias latipes) hoxa2a, like orthologous Hoxa2 genes from other osteichthyans, is expressed during embryogenesis in r2–7 and [...] Read more.
Hoxa2 is an evolutionarily conserved developmental regulatory gene that functions to specify rhombomere (r) and pharyngeal arch (PA) identities throughout the Osteichthyes. Japanese medaka (Oryzias latipes) hoxa2a, like orthologous Hoxa2 genes from other osteichthyans, is expressed during embryogenesis in r2–7 and PA2-7, whereas the paralogous medaka pseudogene, ψhoxa2b, is expressed in noncanonical Hoxa2 domains, including the pectoral fin buds. To understand the evolution of cis-regulatory element (CRE) control of gene expression, we conducted eGFP reporter gene expression studies with extensive functional mapping of several conserved CREs upstream of medaka hoxa2a and ψhoxa2b in transient and stable-line transgenic medaka embryos. The CREs tested were previously shown to contribute to directing mouse Hoxa2 gene expression in r3, r5, and PA2-4. Our results reveal the presence of sequence elements embedded in the medaka hoxa2a and ψhoxa2b upstream enhancer regions (UERs) that mediate expression in r4 and the PAs (hoxa2a r4/CNCC element) or in r3–7 and the PAs ψhoxa2b r3–7/CNCC element), respectively. Further, these elements were shown to be highly conserved among osteichthyans, which suggests that the r4 specifying element embedded in the UER of Hoxa2 is a deeply rooted rhombomere specifying element and the activity of this element has been modified by the evolution of flanking sequences that redirect its activity to alternative developmental compartments. Full article
(This article belongs to the Special Issue Hox Genes and Development)
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Open AccessArticle
Solving Classification Problems for Large Sets of Protein Sequences with the Example of Hox and ParaHox Proteins
J. Dev. Biol. 2016, 4(1), 8; https://doi.org/10.3390/jdb4010008 - 04 Feb 2016
Cited by 2
Abstract
Phylogenetic methods are key to providing models for how a given protein family evolved. However, these methods run into difficulties when sequence divergence is either too low or too high. Here, we provide a case study of Hox and ParaHox proteins so that [...] Read more.
Phylogenetic methods are key to providing models for how a given protein family evolved. However, these methods run into difficulties when sequence divergence is either too low or too high. Here, we provide a case study of Hox and ParaHox proteins so that additional insights can be gained using a new computational approach to help solve old classification problems. For two (Gsx and Cdx) out of three ParaHox proteins the assignments differ between the currently most established view and four alternative scenarios. We use a non-phylogenetic, pairwise-sequence-similarity-based method to assess which of the previous predictions, if any, are best supported by the sequence-similarity relationships between Hox and ParaHox proteins. The overall sequence-similarities show Gsx to be most similar to Hox2–3, and Cdx to be most similar to Hox4–8. The results indicate that a purely pairwise-sequence-similarity-based approach can provide additional information not only when phylogenetic inference methods have insufficient information to provide reliable classifications (as was shown previously for central Hox proteins), but also when the sequence variation is so high that the resulting phylogenetic reconstructions are likely plagued by long-branch-attraction artifacts. Full article
(This article belongs to the Special Issue Hox Genes and Development)
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Review

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Open AccessReview
Regulation of Silk Genes by Hox and Homeodomain Proteins in the Terminal Differentiated Silk Gland of the Silkworm Bombyx mori
J. Dev. Biol. 2016, 4(2), 19; https://doi.org/10.3390/jdb4020019 - 25 May 2016
Cited by 3
Abstract
The silk gland of the silkworm Bombyx mori is a long tubular organ that is divided into several subparts along its anteroposterior (AP) axis. As a trait of terminal differentiation of the silk gland, several silk protein genes are expressed with unique regional [...] Read more.
The silk gland of the silkworm Bombyx mori is a long tubular organ that is divided into several subparts along its anteroposterior (AP) axis. As a trait of terminal differentiation of the silk gland, several silk protein genes are expressed with unique regional specificities. Most of the Hox and some of the homeobox genes are also expressed in the differentiated silk gland with regional specificities. The expression patterns of Hox genes in the silk gland roughly correspond to those in embryogenesis showing “colinearity”. The central Hox class protein Antennapedia (Antp) directly regulates the expression of several middle silk gland–specific silk genes, whereas the Lin-1/Isl-1/Mec3 (LIM)-homeodomain transcriptional factor Arrowhead (Awh) regulates the expression of posterior silk gland–specific genes for silk fiber proteins. We summarize our results and discuss the usefulness of the silk gland of Bombyx mori for analyzing the function of Hox genes. Further analyses of the regulatory mechanisms underlying the region-specific expression of silk genes will provide novel insights into the molecular bases for target-gene selection and regulation by Hox and homeodomain proteins. Full article
(This article belongs to the Special Issue Hox Genes and Development)
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Open AccessReview
Developmental Mechanism of Limb Field Specification along the Anterior–Posterior Axis during Vertebrate Evolution
J. Dev. Biol. 2016, 4(2), 18; https://doi.org/10.3390/jdb4020018 - 19 May 2016
Cited by 5
Abstract
In gnathostomes, limb buds arise from the lateral plate mesoderm at discrete positions along the body axis. Specification of these limb-forming fields can be subdivided into several steps. The lateral plate mesoderm is regionalized into the anterior lateral plate mesoderm (ALPM; cardiac mesoderm) [...] Read more.
In gnathostomes, limb buds arise from the lateral plate mesoderm at discrete positions along the body axis. Specification of these limb-forming fields can be subdivided into several steps. The lateral plate mesoderm is regionalized into the anterior lateral plate mesoderm (ALPM; cardiac mesoderm) and the posterior lateral plate mesoderm (PLPM). Subsequently, Hox genes appear in a nested fashion in the PLPM and provide positional information along the body axis. The lateral plate mesoderm then splits into the somatic and splanchnic layers. In the somatic layer of the PLPM, the expression of limb initiation genes appears in the limb-forming region, leading to limb bud initiation. Furthermore, past and current work in limbless amphioxus and lampreys suggests that evolutionary changes in developmental programs occurred during the acquisition of paired fins during vertebrate evolution. This review presents these recent advances and discusses the mechanisms of limb field specification during development and evolution, with a focus on the role of Hox genes in this process. Full article
(This article belongs to the Special Issue Hox Genes and Development)
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Open AccessReview
Mechanisms of Specificity for Hox Factor Activity
J. Dev. Biol. 2016, 4(2), 16; https://doi.org/10.3390/jdb4020016 - 09 May 2016
Cited by 10
Abstract
Metazoans encode clusters of paralogous Hox genes that are critical for proper development of the body plan. However, there are a number of unresolved issues regarding how paralogous Hox factors achieve specificity to control distinct cell fates. First, how do Hox paralogs, which [...] Read more.
Metazoans encode clusters of paralogous Hox genes that are critical for proper development of the body plan. However, there are a number of unresolved issues regarding how paralogous Hox factors achieve specificity to control distinct cell fates. First, how do Hox paralogs, which have very similar DNA binding preferences in vitro, drive different transcriptional programs in vivo? Second, the number of potential Hox binding sites within the genome is vast compared to the number of sites bound. Hence, what determines where in the genome Hox factors bind? Third, what determines whether a Hox factor will activate or repress a specific target gene? Here, we review the current evidence that is beginning to shed light onto these questions. In particular, we highlight how cooperative interactions with other transcription factors (especially PBC and HMP proteins) and the sequences of cis-regulatory modules provide a basis for the mechanisms of Hox specificity. We conclude by integrating a number of the concepts described throughout the review in a case study of a highly interrogated Drosophila cis-regulatory module named “The Distal-less Conserved Regulatory Element” (DCRE). Full article
(This article belongs to the Special Issue Hox Genes and Development)
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Open AccessReview
Hoxa5: A Key Player in Development and Disease
J. Dev. Biol. 2016, 4(2), 13; https://doi.org/10.3390/jdb4020013 - 25 Mar 2016
Cited by 10
Abstract
A critical position in the developmental hierarchy is occupied by the Hox genes, which encode transcription factors. Hox genes are crucial in specifying regional identity along the embryonic axes and in regulating morphogenesis. In mouse, targeted mutations of Hox genes cause skeletal transformations [...] Read more.
A critical position in the developmental hierarchy is occupied by the Hox genes, which encode transcription factors. Hox genes are crucial in specifying regional identity along the embryonic axes and in regulating morphogenesis. In mouse, targeted mutations of Hox genes cause skeletal transformations and organ defects that can impair viability. Here, we present the current knowledge about the Hoxa5 gene, a paradigm for the function and the regulation of Hox genes. The phenotypic survey of Hoxa5−/− mice has unveiled its critical role in the regional specification of the skeleton and in organogenesis. Most Hoxa5−/− mice die at birth from respiratory distress due to tracheal and lung dysmorphogenesis and impaired diaphragm innervation. The severity of the phenotype establishes that Hoxa5 plays a predominant role in lung organogenesis versus other Hox genes. Hoxa5 also governs digestive tract morphogenesis, thyroid and mammary glands development, and ovary homeostasis. Deregulated Hoxa5 expression is reported in cancers, indicating Hoxa5 involvement in tumor predisposition and progression. The dynamic Hoxa5 expression profile is under the transcriptional control of multiple cis-acting sequences and trans-acting regulators. It is also modulated by epigenetic mechanisms, implicating chromatin modifications and microRNAs. Finally, lncRNAs originating from alternative splicing and distal promoters encompass the Hoxa5 locus. Full article
(This article belongs to the Special Issue Hox Genes and Development)
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Open AccessReview
Hox Genes in Cardiovascular Development and Diseases
J. Dev. Biol. 2016, 4(2), 14; https://doi.org/10.3390/jdb4020014 - 24 Mar 2016
Cited by 3
Abstract
Congenital heart defects (CHD) are the leading cause of death in the first year of life. Over the past 20 years, much effort has been focused on unraveling the genetic bases of CHD. In particular, studies in human genetics coupled with those of [...] Read more.
Congenital heart defects (CHD) are the leading cause of death in the first year of life. Over the past 20 years, much effort has been focused on unraveling the genetic bases of CHD. In particular, studies in human genetics coupled with those of model organisms have provided valuable insights into the gene regulatory networks underlying CHD pathogenesis. Hox genes encode transcription factors that are required for the patterning of the anterior–posterior axis in the embryo. In this review, we focus on the emerging role of anteriorly expressed Hox genes (Hoxa1, Hoxb1, and Hoxa3) in cardiac development, specifically their contribution to patterning of cardiac progenitor cells and formation of the great arteries. Recent evidence regarding the cooperative regulation of heart development by Hox proteins with members of the TALE-class of homeodomain proteins such as Pbx and Meis transcription factors is also discussed. These findings are highly relevant to human pathologies as they pinpoint new genes that increase susceptibility to cardiac anomalies and provide novel mechanistic insights into CHD. Full article
(This article belongs to the Special Issue Hox Genes and Development)
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Open AccessReview
An Overview of Hox Genes in Lophotrochozoa: Evolution and Functionality
J. Dev. Biol. 2016, 4(1), 12; https://doi.org/10.3390/jdb4010012 - 19 Mar 2016
Cited by 6
Abstract
Hox genes are regulators of animal embryonic development. Changes in the number and sequence of Hox genes as well as in their expression patterns have been related to the evolution of the body plan. Lophotrochozoa is a clade of Protostomia characterized by several [...] Read more.
Hox genes are regulators of animal embryonic development. Changes in the number and sequence of Hox genes as well as in their expression patterns have been related to the evolution of the body plan. Lophotrochozoa is a clade of Protostomia characterized by several phyla which show a wide morphological diversity. Despite that the works summarized in this review emphasize the fragmentary nature of the data available regarding the presence and expression of Hox genes, they also offer interesting insight into the evolution of the Hox cluster and the role played by Hox genes in several phyla. However, the number of genes involved in the cluster of the lophotrochozoan ancestor is still a question of debate. The data presented here suggest that at least nine genes were present while two other genes, Lox4 and Post-2, may either have been present in the ancestor or may have arisen as a result of duplication in the Brachiopoda-Mollusca-Annelida lineage. Spatial and temporal collinearity is a feature of Hox gene expression which was probably present in the ancestor of deuterostomes and protostomes. However, in Lophotrochozoa, it has been detected in only a few species belonging to Annelida and Mollusca. Full article
(This article belongs to the Special Issue Hox Genes and Development)
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Open AccessReview
HoxA Genes and the Fin-to-Limb Transition in Vertebrates
J. Dev. Biol. 2016, 4(1), 10; https://doi.org/10.3390/jdb4010010 - 17 Feb 2016
Cited by 8
Abstract
HoxA genes encode for important DNA-binding transcription factors that act during limb development, regulating primarily gene expression and, consequently, morphogenesis and skeletal differentiation. Within these genes, HoxA11 and HoxA13 were proposed to have played an essential role in the enigmatic evolutionary transition from [...] Read more.
HoxA genes encode for important DNA-binding transcription factors that act during limb development, regulating primarily gene expression and, consequently, morphogenesis and skeletal differentiation. Within these genes, HoxA11 and HoxA13 were proposed to have played an essential role in the enigmatic evolutionary transition from fish fins to tetrapod limbs. Indeed, comparative gene expression analyses led to the suggestion that changes in their regulation might have been essential for the diversification of vertebrates’ appendages. In this review, we highlight three potential modifications in the regulation and function of these genes that may have boosted appendage evolution: (1) the expansion of polyalanine repeats in the HoxA11 and HoxA13 proteins; (2) the origin of +a novel long-non-coding RNA with a possible inhibitory function on HoxA11; and (3) the acquisition of cis-regulatory elements modulating 5’ HoxA transcription. We discuss the relevance of these mechanisms for appendage diversification reviewing the current state of the art and performing additional comparative analyses to characterize, in a phylogenetic framework, HoxA11 and HoxA13 expression, alanine composition within the encoded proteins, long-non-coding RNAs and cis-regulatory elements. Full article
(This article belongs to the Special Issue Hox Genes and Development)
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