Reactome: A Curated Pathway Database

Activation of anterior HOX genes in hindbrain development during early embryogenesis

Stable Identifier
Homo sapiens
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In mammals, anterior Hox genes may be defined as paralog groups 1 to 4 (Natale et al. 2011), which are involved in development of the hindbrain through sequential expression in the rhombomeres, transient segments of the neural tube that form during development of the hindbrain (reviewed in Alexander et al. 2009, Soshnikova and Duboule 2009, Tumpel et al. 2009, Mallo et al. 2010, Andrey and Duboule 2014). Hox gene activation during mammalian development has been most thoroughly studied in mouse embryos and the results have been extended to human development by in vitro experiments with human embryonal carcinoma cells and human embryonic stem cells.
Expression of a typical anterior Hox gene has an anterior boundary located at the junction between two rhombomeres and continues caudally to regulate segmentation and segmental fate in ectoderm, mesoderm, and endoderm. Anterior boundaries of expression of successive Hox paralog groups are generally separated from each other by 2 rhombomeres. For example, HOXB2 is expressed in rhombomere 3 (r3) and caudally while HOXB3 is expressed in r5 and caudally. Exceptions exist, however, as HOXA1, HOXA2, and HOXB1 do not follow the rule and HOXD1 and HOXC4 are not expressed in rhombomeres. Hox genes within a Hox cluster are expressed colinearly: the gene at the 3' end of the cluster is expressed earliest, and hence most anteriorly, then genes 5' are activated sequentially in the same order as they occur in the cluster.
Activation of expression occurs epigenetically by loss of polycomb repressive complexes and change of bivalent chromatin to active chromatin through, in part, the actions of trithorax family proteins (reviewed in Soshnikova and Duboule 2009). Hox gene expression initiates in the posterior primitive streak that will contribute to extraembryonic mesoderm. Expression then extends anteriorly into the cells that will become the embryo, where expression is first observed in presumptive lateral plate mesoderm and is transmitted to both paraxial mesoderm and neurectoderm formed by gastrulation along the primitive streak (reviewed in Deschamps et al. 1999, Casaca et al. 2014).
Prior to establishment of the rhombomeres, expression of HOXA1 and HOXB1 is initiated near the future site of r3 and caudally by a gradient of retinoic acid (RA). (Mechanisms of retinoic acid signaling are reviewed in Cunningham and Duester 2015.) The RA is generated by the ALDH1A2 (RALDH2) enzyme located in somites flanking the caudal hindbrain and degraded by CYP26 enzymes expressed initially in anterior neural ectoderm of the early gastrula and then throughout most of the hindbrain (reviewed in White and Schilling 2008). HOXA1 with PBX1,2 and MEIS2 directly activate transcription of ALDH1A2 to maintain retinoic acid synthesis in the somitic mesoderm (Vitobello et al. 2011). Differentiation of embryonal carcinoma cells and embryonic stem cells in response to retinoic acid is used to model the process of differentiation in vitro (reviewed in Soprano et al. 2007, Gudas et al. 2013).
HOXA1 appears to set the anterior limit of HOXB1 expression (Barrow et al. 2000). HOXB1 initiates expression of EGR2 (KROX20) in presumptive r3. EGR2 then activates HOXA2 expression in r3 and r5 while HOXB1, together with PBX1 and MEIS:PKNOX1 (MEIS:PREP), activates expression of HOXA2 in r4 and caudal rhombomeres. AP-2 transcription factors maintain expression of HOXA2 in neural crest cells (Maconochie et al. 1999). HOXB1 also activates expression of HOXB2 in r3 and caudal rhombomeres. EGR2 negatively regulates HOXB1 so that by the time rhombomeres appear, HOXB1 is restricted to r4 and HOXA1 is no longer detectable (Barrow et al. 2000). EGR2 and MAFB (Kreisler) then activate HOXA3 and HOXB3 in r5 and caudal rhombomeres. Retinoic acid activates HOXA4, HOXB4, and HOXD4 in r7, the final rhombomere. HOX proteins, in turn, activate expression of genes in combination with other factors, notably members of the TALE family of transcription factors (PBX, PREP, and MEIS, reviewed in Schulte and Frank 2014, Rezsohazy et al. 2015). HOX proteins also participate in non-transcriptional interactions (reviewed in Rezsohazy 2014). In zebrafish, Xenopus, and chicken factors such as Meis3, Fgf3, Fgf8, and vHNF regulate anterior hox genes (reviewed in Schulte and Frank 2014), however less is known about the roles of homologous factors in mammals.
Mutations in HOXA1 in humans have been observed to cause developmental abnormalities located mostly in the head and neck region (Tischfield et al. 2005, Bosley et al. 2008). A missense mutation in HOXA2 causes microtia, hearing impairment, and partially cleft palate (Alasti et al. 2008). A missense mutation in HOXB1 causes a similar phenotype to the Hoxb1 null mutation in mice: bilateral facial palsy, hearing loss, and strabismus (improper alignment of the eyes) (Webb et al. 2012).

Literature References
PubMed ID Title Journal Year
25560970 Mechanisms of retinoic acid signalling and its roles in organ and limb development Nat. Rev. Mol. Cell Biol. 2015
18816852 How degrading: Cyp26s in hindbrain development Dev. Dyn. 2008
18412118 The clinical spectrum of homozygous HOXA1 mutations Am. J. Med. Genet. A 2008
18394579 A mutation in HOXA2 is responsible for autosomal-recessive microtia in an Iranian family Am. J. Hum. Genet. 2008
22770981 HOXB1 founder mutation in humans recapitulates the phenotype of Hoxb1-/- mice Am. J. Hum. Genet. 2012
16155570 Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development Nat. Genet. 2005
25804734 Cellular and molecular insights into Hox protein action Development 2015
21497760 Hox and Pbx factors control retinoic acid synthesis during hindbrain segmentation Dev. Cell 2011
10662633 Roles of Hoxa1 and Hoxa2 in patterning the early hindbrain of the mouse Development 2000
10668974 Initiation, establishment and maintenance of Hox gene expression patterns in the mouse Int. J. Dev. Biol. 1999
24529385 SnapShot: Hox gene regulation Cell 2014
20435029 Hox genes and regional patterning of the vertebrate body plan Dev. Biol. 2010
19923920 Epigenetic regulation of vertebrate Hox genes: a dynamic equilibrium Epigenetics 2009
24115586 Non-transcriptional interactions of Hox proteins: inventory, facts, and future directions Dev. Dyn. 2014
23973942 Retinoids induce stem cell differentiation via epigenetic changes Semin. Cell Dev. Biol. 2013
19575673 Hox genes and segmentation of the hindbrain and axial skeleton Annu. Rev. Cell Dev. Biol. 2009
17368312 Role of retinoic acid in the differentiation of embryonal carcinoma and embryonic stem cells Vitam. Horm. 2007
19651303 Hox genes and segmentation of the vertebrate hindbrain Curr. Top. Dev. Biol. 2009
10068641 Regulation of Hoxa2 in cranial neural crest cells involves members of the AP-2 family Development 1999
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