Developmental Signals - Homeobox

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Introduction

Proposed Hox protein classification
Proposed Hox protein classification[1]

The family of homeobox (Hox) proteins has been a focus of research for over 30 years. In humans, the homeobox gene family contains about 235 functional genes and 65 pseudogenes. This family of genes were also the basis of the embryo patterning studies that led to the Nobel Prize in Medicine 1995. We now know that in addition to whole embryo axes patterning, this family of genes has many roles in establishing pattern throughout the embryo in different tissues and organs.


There has recently been a revival of an earlier theory[2] that Hox expression during vertebrate pattern formation is linked to the process of segmentation of paraxial mesoderm during somitogenesis.[3]


This signalling pathway has also been implicated in many developmental abnormalities and diseases.

Fly wild-type head.jpg Fly antennapedia head.jpg
Fly wild-type head Fly antennapedia head


Factor Links: AMH | hCG | BMP | sonic hedgehog | bHLH | HOX | FGF | FOX | Hippo | LIM | Nanog | NGF | Nodal | Notch | PAX | retinoic acid | SIX | Slit2/Robo1 | SOX | TBX | TGF-beta | VEGF | WNT | Category:Molecular

| Category:Hox

Some Recent Findings

Model Hox10 kidney development
Mouse Hoxa5 expression
Mouse Hoxa5 expression (E12.5)[4]
  • Hox genes in the pharyngeal region: how Hoxa3 controls early embryonic development of the pharyngeal organs[5] "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"
  • A single three-dimensional chromatin compartment in amphioxus indicates a stepwise evolution of vertebrate Hox bimodal regulation[6] "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. ...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."
  • Homeobox Genes of Caenorhabditis elegans and Spatio-Temporal Expression[7] "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." Worm Development
More recent papers  
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More? References | Discussion Page | Journal Searches | 2019 References

Search term: Hox

Older papers  
These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.

See also the Discussion Page for other references listed by year and References on this current page.

  • A Hox regulatory network of hindbrain segmentation is conserved to the base of vertebrates[8] "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."
  • Hoxb1b controls oriented cell division, cell shape and microtubule dynamics in neural tube morphogenesis[9] "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. ...Hoxb1b regulates mitotic spindle rotation during the oriented neural keel symmetric mitoses that are required for normal neural tube lumen formation in the zebrafish."
  • Evolution of anterior Hox regulatory elements among chordates[10] "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. ...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."
  • Hox10 Genes Function in Kidney Development in the Differentiation and Integration of the Cortical Stroma [11] "Consistent with loss of cortical stromal cell function, Hox10 mutant kidneys display reduced and aberrant ureter branching, decreased nephrogenesis. These data therefore provide critical novel insights into the cellular and genetic mechanisms governing cortical cell development during kidney organogenesis. These results, combined with previous evidence demonstrating that Hox11 genes are necessary for patterning the metanephric mesenchyme, support a model whereby distinct populations in the nephrogenic cord are regulated by unique Hox codes, and that differential Hox function along the AP axis of the nephrogenic cord is critical for the differentiation and integration of these cell types during kidney organogenesis."
  • Proposed Hox protein classification[1] "Our classification scheme offers a higher-resolution classification that is in accordance with phylogenetic as well as experimental data and, thereby, provides a novel basis for experiments, such as comparative and functional analyses of Hox-proteins."
  • Homeobox A7 up-regulation of epidermal growth factor receptor expression in human granulosa cells[12] "Our present study reveals a novel mechanistic role for HOXA7 in modulating granulosa cell proliferation via the regulation of EGFR. This finding contributes to the knowledge of the pro-proliferation effect of HOXA7 in granulosa cell growth and differentiation."
  • Hoxa5 transcriptional complexity in the mouse embryo[4] "Our observation that the Hoxa5 larger transcripts possess a developmentally-regulated expression combined to the increasing sum of data on the role of long noncoding RNAs in transcriptional regulation suggest that the Hoxa5 larger transcripts may participate in the control of Hox gene expression."

Classification

Proposed Hox protein classification.jpg
Proposed Hox protein classification[1]


Human Hox

Ideograms Human homeobox genes

Chromosomal Distribution of Human Homeobox Genes[13]


Functions

Developmental patterning signal.

Neural

Segmentation

Hindbrain neural crest migration.jpg

Hindbrain neural crest migration and Hox expression pattern[14]


A schematic diagram of a chick head at embryonic day two (Hamburger Hamilton Stages), showing pathways of neural crest migration in the chick and mouse embryo and patterns of Hox gene expression in the pharyngeal arches. Hox genes are expressed in neural crest cells, which emigrate predominantly from even-numbered rhombomeres into the pharyngeal (branchial) arches generating skeletal tissues and cranial ganglia.


Note that the first pharyngeal arch is free of Hox expression.

Legend

  • PA - pharyngeal arch
  • Md - mandibular part of pharyngeal arch 1
  • Mx - maxillary part of pharyngeal arch 1
  • OV - otic vesicle
  • r - rhombomere

Adapted by permission from Macmillan Publishers Ltd: Nature Reviews Neuroscience[14], copyright (2007)

Links: Neural System Development | Neural Crest Development

Phrenic Motor Neurons

Hox5 (Hoxa5 and Hoxc5) required for phrenic motor column (PMC) development that form the respiratory motor neurons driving the diaphragm for respiration.[15]


Links: Respiratory System Development

Axial Skeleton

Vertebra ossification sequence.jpg

Vertebral element ossification between species.[16]

Hox 3 phase model.jpg

Chicken model of Hox in paraxial mesoderm precursors in the epiblast/tail-bud during axis elongation[17]


Links: Somitogenesis | Axial Skeleton Development

Limb

Limb patterning factors 08.jpg

Mouse Limb Patterning Fgf and Hox Expression[18]

Fgf and Hox expression in E10.5 to 10.75 wild-type embryonic forelimb autopod, compared to future E14.5 digit arrangement.

Hoxa gene expression in limb bud 01.jpg

Expression of Hoxa4, Hoxa9, Hoxa10, Hoxa11, Hoxa11 antisense (Hoxa11as), and Hoxa13 in E12.5 limb buds.[19]

Links: Limb Development

Other

Signaling Pathway

Otx

Otx is a txanscription factor essential for the normal development of the brain, cerebellum, pineal gland, and eye.

OTX is a homeobox family gene related to a gene expressed in the developing Drosophila head termed 'orthodenticle.' OTX transcription factors bind with high affinity to TAATCC/T elements on DNA.


OMIM: OTX1 | OTX2 | OTX3
Links: Pineal | Vision | PubMed - Otx

Additional Images

References

  1. 1.0 1.1 1.2 Hueber SD, Weiller GF, Djordjevic MA & Frickey T. (2010). Improving Hox protein classification across the major model organisms. PLoS ONE , 5, e10820. PMID: 20520839 DOI.
  2. Meinhardt H. Models For Biological Pattern Formation. Academic Press; 1982.
  3. Gu S, Gu W, Shou J, Xiong J, Liu X, Sun B, Yang D & Xie R. (2017). The Molecular Feature of HOX Gene Family in the Intramedullary Spinal Tumors. Spine , 42, 291-297. PMID: 25785959 DOI.
  4. 4.0 4.1 Coulombe Y, Lemieux M, Moreau J, Aubin J, Joksimovic M, Bérubé-Simard FA, Tabariès S, Boucherat O, Guillou F, Larochelle C, Tuggle CK & Jeannotte L. (2010). Multiple promoters and alternative splicing: Hoxa5 transcriptional complexity in the mouse embryo. PLoS ONE , 5, e10600. PMID: 20485555 DOI.
  5. Gordon J. (2018). Hox genes in the pharyngeal region: how Hoxa3 controls early embryonic development of the pharyngeal organs. Int. J. Dev. Biol. , 62, 775-783. PMID: 30604847 DOI.
  6. Acemel RD, Tena JJ, Irastorza-Azcarate I, Marlétaz F, Gómez-Marín C, de la Calle-Mustienes E, Bertrand S, Diaz SG, Aldea D, Aury JM, Mangenot S, Holland PW, Devos DP, Maeso I, Escrivá H & Gómez-Skarmeta JL. (2016). A single three-dimensional chromatin compartment in amphioxus indicates a stepwise evolution of vertebrate Hox bimodal regulation. Nat. Genet. , 48, 336-41. PMID: 26829752 DOI.
  7. Hench J, Henriksson J, Abou-Zied AM, Lüppert M, Dethlefsen J, Mukherjee K, Tong YG, Tang L, Gangishetti U, Baillie DL & Bürglin TR. (2015). The Homeobox Genes of Caenorhabditis elegans and Insights into Their Spatio-Temporal Expression Dynamics during Embryogenesis. PLoS ONE , 10, e0126947. PMID: 26024448 DOI.
  8. Parker HJ, Bronner ME & Krumlauf R. (2014). A Hox regulatory network of hindbrain segmentation is conserved to the base of vertebrates. Nature , 514, 490-3. PMID: 25219855 DOI.
  9. Zigman M, Laumann-Lipp N, Titus T, Postlethwait J & Moens CB. (2014). Hoxb1b controls oriented cell division, cell shape and microtubule dynamics in neural tube morphogenesis. Development , 141, 639-49. PMID: 24449840 DOI.
  10. Natale A, Sims C, Chiusano ML, Amoroso A, D'Aniello E, Fucci L, Krumlauf R, Branno M & Locascio A. (2011). Evolution of anterior Hox regulatory elements among chordates. BMC Evol. Biol. , 11, 330. PMID: 22085760 DOI.
  11. Yallowitz AR, Hrycaj SM, Short KM, Smyth IM & Wellik DM. (2011). Hox10 genes function in kidney development in the differentiation and integration of the cortical stroma. PLoS ONE , 6, e23410. PMID: 21858105 DOI.
  12. Zhang Y, Huang Q, Cheng JC, Nishi Y, Yanase T, Huang HF & Leung PC. (2010). Homeobox A7 increases cell proliferation by up-regulation of epidermal growth factor receptor expression in human granulosa cells. Reprod. Biol. Endocrinol. , 8, 61. PMID: 20540809 DOI.
  13. Holland PW, Booth HA & Bruford EA. (2007). Classification and nomenclature of all human homeobox genes. BMC Biol. , 5, 47. PMID: 17963489 DOI.
  14. 14.0 14.1 Guthrie S. (2007). Patterning and axon guidance of cranial motor neurons. Nat. Rev. Neurosci. , 8, 859-71. PMID: 17948031 DOI.
  15. Philippidou P, Walsh CM, Aubin J, Jeannotte L & Dasen JS. (2012). Sustained Hox5 gene activity is required for respiratory motor neuron development. Nat. Neurosci. , 15, 1636-44. PMID: 23103965 DOI.
  16. Hautier L, Weisbecker V, Sánchez-Villagra MR, Goswami A & Asher RJ. (2010). Skeletal development in sloths and the evolution of mammalian vertebral patterning. Proc. Natl. Acad. Sci. U.S.A. , 107, 18903-8. PMID: 20956304 DOI.
  17. Denans N, Iimura T & Pourquié O. (2015). Hox genes control vertebrate body elongation by collinear Wnt repression. Elife , 4, . PMID: 25719209 DOI.
  18. Galli A, Robay D, Osterwalder M, Bao X, Bénazet JD, Tariq M, Paro R, Mackem S & Zeller R. (2010). Distinct roles of Hand2 in initiating polarity and posterior Shh expression during the onset of mouse limb bud development. PLoS Genet. , 6, e1000901. PMID: 20386744 DOI.
  19. Woltering JM, Noordermeer D, Leleu M & Duboule D. (2014). Conservation and divergence of regulatory strategies at Hox Loci and the origin of tetrapod digits. PLoS Biol. , 12, e1001773. PMID: 24465181 DOI.


Reviews

Mallo M, Wellik DM & Deschamps J. (2010). Hox genes and regional patterning of the vertebrate body plan. Dev. Biol. , 344, 7-15. PMID: 20435029 DOI.

Narita Y & Rijli FM. (2009). Hox genes in neural patterning and circuit formation in the mouse hindbrain. Curr. Top. Dev. Biol. , 88, 139-67. PMID: 19651304 DOI.

Deschamps J & van Nes J. (2005). Developmental regulation of the Hox genes during axial morphogenesis in the mouse. Development , 132, 2931-42. PMID: 15944185 DOI.

Schilling TF & Knight RD. (2001). Origins of anteroposterior patterning and Hox gene regulation during chordate evolution. Philos. Trans. R. Soc. Lond., B, Biol. Sci. , 356, 1599-613. PMID: 11604126 DOI.

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Cite this page: Hill, M.A. (2019, July 19) Embryology Developmental Signals - Homeobox. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Developmental_Signals_-_Homeobox

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