Talk:Developmental Signals - Homeobox

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Cite this page: Hill, M.A. (2019, October 18) Embryology Developmental Signals - Homeobox. Retrieved from

Search All Databases hox

PMID 20485555


Hox genes in the pharyngeal region: how Hoxa3 controls early embryonic development of the pharyngeal organs

Int J Dev Biol. 2018;62(11-12):775-783. doi: 10.1387/ijdb.180284jg.

Gordon J1.

Abstract The pharyngeal organs, namely the thyroid, thymus, parathyroids, and ultimobranchial bodies, derive from the pharyngeal endoderm during embryonic development. The pharyngeal region is a segmented structure comprised of a series of reiterated structures: the pharyngeal arches on the exterior surface, the pharyngeal pouches on the interior, and a mesenchymal core. It is well known that Hox genes control spatial identity along the anterior-posterior axis of the developing vertebrate embryo, and nowhere is this is more evident than in the pharyngeal region. Each of the distinct segmented regions has a unique pattern of Hox expression, which conveys crucial positional information to the cells and tissues within it. In the context of pharyngeal organ development, molecular data suggest that HOXA3 is responsible for specifying organ identity within the third pharyngeal pouch, and in its absence, thymus and parathyroid organogenesis fails to proceed normally. Recent studies comprising a series of Hoxa3 mutations identified specific spatial and temporal roles for HOXA3 in pharyngeal organ development, including both cell-autonomous and non-autonomous functions, revealing a system that is more complex than originally thought. Here, we will review the current understanding of the role of Hox genes in the early embryonic development of the pharyngeal organs in the mouse, with a particular focus on the function of HOXA3 in thymus and parathyroid organogenesis.

PMID: 30604847 DOI: 10.1387/ijdb.180284jg


Diversity of human and mouse homeobox gene expression in development and adult tissues

BMC Dev Biol. 2016 Nov 3;16(1):40.

Dunwell TL1, Holland PW2.

  • 20 human homeobox genes with widespread expression, primarily from the TALE, CERS and ZF classes.
  • Human - 8-cell and morula - 12 eutherian-specific homeobox genes not detectable outside of reproductive tissues or the embryo.
  • Mouse - four phases of homeobox gene expression - oocyte to zygote; 2-cell; 4-cell to blastocyst; early to mid post-implantation. The most dramatic shifts in homeobox gene expression are between 2-cell and 4-cell, and between blastocyst and post-implantation. Within this group there is a gradual shift in expression between e8.5 and e9.5 dominated by new expression of HOXL ANTP class genes.


BACKGROUND: Homeobox genes encode a diverse set of transcription factors implicated in a vast range of biological processes including, but not limited to, embryonic cell fate specification and patterning. Although numerous studies report expression of particular sets of homeobox genes, a systematic analysis of the tissue specificity of homeobox genes is lacking. RESULTS: Here we analyse publicly-available transcriptome data from human and mouse developmental stages, and adult human tissues, to identify groups of homeobox genes with similar expression patterns. We calculate expression profiles for 242 human and 278 mouse homeobox loci across a combination of 59 human and 12 mouse adult tissues, early and late developmental stages. This revealed 20 human homeobox genes with widespread expression, primarily from the TALE, CERS and ZF classes. Most homeobox genes, however, have greater tissue-specificity, allowing us to compile homeobox gene expression lists for neural tissues, immune tissues, reproductive and developmental samples, and for numerous organ systems. In mouse development, we propose four distinct phases of homeobox gene expression: oocyte to zygote; 2-cell; 4-cell to blastocyst; early to mid post-implantation. The final phase change is marked by expression of ANTP class genes. We also use these data to compare expression specificity between evolutionarily-based gene classes, revealing that ANTP, PRD, LIM and POU homeobox gene classes have highest tissue specificity while HNF, TALE, CUT and CERS are most widely expressed. CONCLUSIONS: The homeobox genes comprise a large superclass and their expression patterns are correspondingly diverse, although in a broad sense related to an evolutionarily-based classification. The ubiquitous expression of some genes suggests roles in general cellular processes; in contrast, most human homeobox genes have greater tissue specificity and we compile useful homeobox datasets for particular tissues, organs and developmental stages. The identification of a set of eutherian-specific homeobox genes peaking from human 8-cell to morula stages suggests co-option of new genes to new developmental roles in evolution. KEYWORDS: Embryo; Homeodomain; Organs; Transcription factor PMID: 27809766 PMCID: PMC5094009 DOI: 10.1186/s12861-016-0140-y

A single three-dimensional chromatin compartment in amphioxus indicates a stepwise evolution of vertebrate Hox bimodal regulation

Nat Genet. 2016 Feb 1. doi: 10.1038/ng.3497. [Epub ahead of print]

Acemel RD1, Tena JJ1, Irastorza-Azcarate I1, Marlétaz F2, Gómez-Marín C1, de la Calle-Mustienes E1, Bertrand S3, Diaz SG1, Aldea D3, Aury JM4, Mangenot S4, Holland PW2, Devos DP1, Maeso I1, Escrivá H3, Gómez-Skarmeta JL1.


The HoxA and HoxD gene clusters of jawed vertebrates are organized into bipartite three-dimensional chromatin structures that separate long-range regulatory inputs coming from the anterior and posterior Hox-neighboring regions. This architecture is instrumental in allowing vertebrate Hox genes to pattern disparate parts of the body, including limbs. Almost nothing is known about how these three-dimensional topologies originated. Here we perform extensive 4C-seq profiling of the Hox cluster in embryos of amphioxus, an invertebrate chordate. We find that, in contrast to the architecture in vertebrates, the amphioxus Hox cluster is organized into a single chromatin interaction domain that includes long-range contacts mostly from the anterior side, bringing distant cis-regulatory elements into contact with Hox genes. We infer that the vertebrate Hox bipartite regulatory system is an evolutionary novelty generated by combining ancient long-range regulatory contacts from DNA in the anterior Hox neighborhood with new regulatory inputs from the posterior side. PMID 26829752


The Homeobox Genes of Caenorhabditis elegans and Insights into Their Spatio-Temporal Expression Dynamics during Embryogenesis

PLoS One. 2015 May 29;10(5):e0126947. doi: 10.1371/journal.pone.0126947.

Hench J1, Henriksson J1, Abou-Zied AM1, Lüppert M1, Dethlefsen J1, Mukherjee K1, Tong YG1, Tang L1, Gangishetti U2, Baillie DL3, Bürglin TR1.


Homeobox genes play crucial roles for the development of multicellular eukaryotes. We have generated a revised list of all homeobox genes for Caenorhabditis elegans and provide a nomenclature for the previously unnamed ones. We show that, out of 103 homeobox genes, 70 are co-orthologous to human homeobox genes. 14 are highly divergent, lacking an obvious ortholog even in other Caenorhabditis species. One of these homeobox genes encodes 12 homeodomains, while three other highly divergent homeobox genes encode a novel type of double homeodomain, termed HOCHOB. To understand how transcription factors regulate cell fate during development, precise spatio-temporal expression data need to be obtained. Using a new imaging framework that we developed, Endrov, we have generated spatio-temporal expression profiles during embryogenesis of over 60 homeobox genes, as well as a number of other developmental control genes using GFP reporters. We used dynamic feedback during recording to automatically adjust the camera exposure time in order to increase the dynamic range beyond the limitations of the camera. We have applied the new framework to examine homeobox gene expression patterns and provide an analysis of these patterns. The methods we developed to analyze and quantify expression data are not only suitable for C. elegans, but can be applied to other model systems or even to tissue culture systems.

PMID 26024448

The Intersection of the Extrinsic Hedgehog and WNT/Wingless Signals with the Intrinsic Hox Code Underpins Branching Pattern and Tube Shape Diversity in the Drosophila Airways

PLoS Genet. 2015 Jan 23;11(1):e1004929. doi: 10.1371/journal.pgen.1004929. eCollection 2015.

Matsuda R1, Hosono C1, Saigo K2, Samakovlis C3.


The tubular networks of the Drosophila respiratory system and our vasculature show distinct branching patterns and tube shapes in different body regions. These local variations are crucial for organ function and organismal fitness. Organotypic patterns and tube geometries in branched networks are typically controlled by variations of extrinsic signaling but the impact of intrinsic factors on branch patterns and shapes is not well explored. Here, we show that the intersection of extrinsic hedgehog(hh) and WNT/wingless (wg) signaling with the tube-intrinsic Hox code of distinct segments specifies the tube pattern and shape of the Drosophila airways. In the cephalic part of the airways, hh signaling induces expression of the transcription factor (TF) knirps (kni) in the anterior dorsal trunk (DTa1). kni represses the expression of another TF spalt major (salm), making DTa1 a narrow and long tube. In DTa branches of more posterior metameres, Bithorax Complex (BX-C) Hox genes autonomously divert hh signaling from inducing kni, thereby allowing DTa branches to develop as salm-dependent thick and short tubes. Moreover, the differential expression of BX-C genes is partly responsible for the anterior-to-posterior gradual increase of the DT tube diameter through regulating the expression level of Salm, a transcriptional target of WNT/wg signaling. Thus, our results highlight how tube intrinsic differential competence can diversify tube morphology without changing availabilities of extrinsic factors.

PMID 25615601


A Hox regulatory network of hindbrain segmentation is conserved to the base of vertebrates

Nature. 2014 Oct 23;514(7523):490-3. doi: 10.1038/nature13723. Epub 2014 Sep 14.

Parker HJ1, Bronner ME2, Krumlauf R3.


A defining feature governing head patterning of jawed vertebrates is a highly conserved gene regulatory network that integrates hindbrain segmentation with segmentally restricted domains of Hox gene expression. Although non-vertebrate chordates display nested domains of axial Hox expression, they lack hindbrain segmentation. The sea lamprey, a jawless fish, can provide unique insights into vertebrate origins owing to its phylogenetic position at the base of the vertebrate tree. It has been suggested that lamprey may represent an intermediate state where nested Hox expression has not been coupled to the process of hindbrain segmentation. However, little is known about the regulatory network underlying Hox expression in lamprey or its relationship to hindbrain segmentation. Here, using a novel tool that allows cross-species comparisons of regulatory elements between jawed and jawless vertebrates, we report deep conservation of both upstream regulators and segmental activity of enhancer elements across these distant species. Regulatory regions from diverse gnathostomes drive segmental reporter expression in the lamprey hindbrain and require the same transcriptional inputs (for example, Kreisler (also known as Mafba), Krox20 (also known as Egr2a)) in both lamprey and zebrafish. We find that lamprey hox genes display dynamic segmentally restricted domains of expression; we also isolated a conserved exonic hox2 enhancer from lamprey that drives segmental expression in rhombomeres 2 and 4. Our results show that coupling of Hox gene expression to segmentation of the hindbrain is an ancient trait with origin at the base of vertebrates that probably led to the formation of rhombomeric compartments with an underlying Hox code. PMID 25219855

Hoxb1b controls oriented cell division, cell shape and microtubule dynamics in neural tube morphogenesis

Development. 2014 Feb;141(3):639-49. doi: 10.1242/dev.098731.

Zigman M1, Laumann-Lipp N, Titus T, Postlethwait J, Moens CB. Author information


Hox genes are classically ascribed to function in patterning the anterior-posterior axis of bilaterian animals; however, their role in directing molecular mechanisms underlying morphogenesis at the cellular level remains largely unstudied. We unveil a non-classical role for the zebrafish hoxb1b gene, which shares ancestral functions with mammalian Hoxa1, in controlling progenitor cell shape and oriented cell division during zebrafish anterior hindbrain neural tube morphogenesis. This is likely distinct from its role in cell fate acquisition and segment boundary formation. We show that, without affecting major components of apico-basal or planar cell polarity, Hoxb1b regulates mitotic spindle rotation during the oriented neural keel symmetric mitoses that are required for normal neural tube lumen formation in the zebrafish. This function correlates with a non-cell-autonomous requirement for Hoxb1b in regulating microtubule plus-end dynamics in progenitor cells in interphase. We propose that Hox genes can influence global tissue morphogenesis by control of microtubule dynamics in individual cells in vivo. KEYWORDS: Cell polarity, Hoxa1, Hoxb1b, In vivo tissue morphogenesis, Neural tube formation, Oriented cell division, Zebrafish

PMID 24449840


Evolution of anterior Hox regulatory elements among chordates

BMC Evol Biol. 2011 Nov 15;11:330.

Natale A, Sims C, Chiusano ML, Amoroso A, D'Aniello E, Fucci L, Krumlauf R, Branno M, Locascio A. Source Laboratory of Cellular and Developmental Biology, Stazione Zoologica Anton Dohrn, Villa Comunale, Naples, Italy. Abstract BACKGROUND: The Hox family of transcription factors has a fundamental role in segmentation pathways and axial patterning of embryonic development and their clustered organization is linked with the regulatory mechanisms governing their coordinated expression along embryonic axes. Among chordates, of particular interest are the Hox paralogous genes in groups 1-4 since their expression is coupled to the control of regional identity in the anterior nervous system, where the highest structural diversity is observed. RESULTS: To investigate the degree of conservation in cis-regulatory components that form the basis of Hox expression in the anterior nervous system, we have used assays for transcriptional activity in ascidians and vertebrates to compare and contrast regulatory potential. We identified four regulatory sequences located near the CiHox1, CiHox2 and CiHox4 genes of the ascidian Ciona intestinalis which direct neural specific domains of expression. Using functional assays in Ciona and vertebrate embryos in combination with sequence analyses of enhancer fragments located in similar positions adjacent to Hox paralogy group genes, we compared the activity of these four Ciona cis-elements with a series of neural specific enhancers from the amphioxus Hox1-3 genes and from mouse Hox paralogous groups 1-4. CONCLUSIONS: This analysis revealed that Kreisler and Krox20 dependent enhancers critical in segmental regulation of the hindbrain appear to be specific for the vertebrate lineage. In contrast, neural enhancers that function as Hox response elements through the action of Hox/Pbx binding motifs have been conserved during chordate evolution. The functional assays reveal that these Hox response cis-elements are recognized by the regulatory components of different and extant species. Together, our results indicate that during chordate evolution, cis-elements dependent upon Hox/Pbx regulatory complexes, are responsible for key aspects of segmental Hox expression in neural tissue and appeared with urochordates after cephalochordate divergence.

PMID 22085760


Hedgehog signaling is dispensable for adult murine hematopoietic stem cell function and hematopoiesis

Cell Stem Cell. 2009 Jun 5;4(6):559-67.

Hofmann I, Stover EH, Cullen DE, Mao J, Morgan KJ, Lee BH, Kharas MG, Miller PG, Cornejo MG, Okabe R, Armstrong SA, Ghilardi N, Gould S, de Sauvage FJ, McMahon AP, Gilliland DG. Source Division of Hematology, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.


We report the unexpected finding that loss of Hh signaling through conditional deletion of Smoothened (Smo) in the adult hematopoietic compartment has no apparent effect on adult hematopoiesis, including peripheral blood count, number or cell-cycle status of stem or progenitor cells, hematopoietic colony-forming potential, long-term repopulating activity in competitive repopulation assays, or stress response to serial 5-fluorouracil treatment. Furthermore, pharmacologic inhibition of Hh signaling with a potent and selective small molecule antagonist has no substantive effect on hematopoiesis in the mouse. In addition, Hh signaling is not required for the development of MLL-AF9-mediated acute myeloid leukemia (AML). Taken together, these data demonstrate that Hh signaling is dispensable for normal hematopoietic development and hematopoietic stem cell function, indicating that targeting of Hh signaling in solid tumors is not likely to result in hematopoietic toxicity. Furthermore, the Hh pathway may not be a compelling target in certain hematopoietic malignancies.

Comment in Cell Stem Cell. 2009 Jun 5;4(6):470-1.

PMID 19497284


Hox transcription factors and their elusive mammalian gene targets

Heredity. 2006 Aug;97(2):88-96. Epub 2006 May 24.

Svingen T, Tonissen KF. Source Cell Biology Group, Eskitis Institute for Cell and Molecular Therapies and School of Biomolecular and Biomedical Science, Griffith University, Nathan, Queensland 4111, Australia.


The Hox family of homeodomain transcription factors regulate numerous pathways during developmental and normal cellular processes. All Hox proteins recognise similar sequences in vitro yet display functional diversity in an in vivo environment. This review focuses on the transcriptional and functional specificity elicited by Hox proteins, giving an overview of homeodomain-DNA interactions and the gain of binding specificity through cooperative binding with cofactors. Furthermore, currently identified mammalian Hox target genes are presented, of which the most striking feature is that very few direct Hox targets have been identified. The direct targets participate in an array of cellular functions including organogenesis and cellular differentiation, cell adhesion and migration and cell cycle and apoptotic pathways. A further assessment of identified mammalian promoter targets and the contribution of bases outside the canonical recognition motif is given, highlighting roles they may play in either trans-activation or repression by Hox proteins.

PMID 16721389

The list contains likely Hox gene targets and the Hox protein responsible for the trans-regulatory effect. The (+/-) symbols represent either a positive or negative regulatory effect on the target gene and (?) symbol indicates an unknown effect. Also, note that although there is some experimental evidence to suggest all are likely direct gene targets, not all have been exclusively verified of being so through in vivo experiments. The corresponding reference(s) for each gene target is also shown.

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Hox protein






Kutejova et al (2005)


Raman et al (2000a)

HOXA5  Human 
HOXA5+Progesterone receptorHuman

Raman et al (2000b)


Chen et al (2005)


Foucher et al (2002); Gao et al (2002)


Shi et al (1999, 2001)


Bruhl et al (2004)


Bromleigh and Freedman (2000)

HOXA10+ beta 3-IntegrinHuman

Daftary et al (2002)


Troy et al (2003)


Kim et al (2003)

Hoxa13, Hoxd13+EphA7Mouse

Salsi and Zappavigna (2006)


Penkov et al (2000)


Guazzi et al (1994)


Safaei (1997)


Wu et al (2003)


Carè et al (1996)


Jones et al (1992)


Jones et al (1992)


Tomotsune et al (1993)


Tkatchenko et al (2001)

Hoxd10, b6, b7, b9, c8+ReninMouse

Pan et al (2004)


Developmental regulation of the Hox genes during axial morphogenesis in the mouse

Development. 2005 Jul;132(13):2931-42.

Deschamps J, van Nes J. Source Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.


The Hox genes confer positional information to the axial and paraxial tissues as they emerge gradually from the posterior aspect of the vertebrate embryo. Hox genes are sequentially activated in time and space, in a way that reflects their organisation into clusters in the genome. Although this co-linearity of expression of the Hox genes has been conserved during evolution, it is a phenomenon that is still not understood at the molecular level. This review aims to bring together recent findings that have advanced our understanding of the regulation of the Hox genes during mouse embryonic development. In particular, we highlight the integration of these transducers of anteroposterior positional information into the genetic network that drives tissue generation and patterning during axial elongation.

PMID 15944185