scholarly journals Hoxa1 and Hoxb1 synergize in patterning the hindbrain, cranial nerves and second pharyngeal arch

Development ◽  
1998 ◽  
Vol 125 (6) ◽  
pp. 1123-1136 ◽  
Author(s):  
A. Gavalas ◽  
M. Studer ◽  
A. Lumsden ◽  
F.M. Rijli ◽  
R. Krumlauf ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Motor Nerve ◽  
Cranial Nerves ◽  
Neural Crest Cell ◽  
Pharyngeal Arch ◽  
Retrograde Labelling ◽  
Complete Disruption ◽  
Middle Ear Development ◽  
Crest Cell ◽  
Null Mutants

The analysis of Hoxa1 and Hoxb1 null mutants suggested that these genes are involved in distinct aspects of hindbrain segmentation and specification. Here we investigate the possible functional synergy of the two genes. The generation of Hoxa1(3′RARE)/Hoxb1(3′RARE) compound mutants resulted in mild facial motor nerve defects reminiscent of those present in the Hoxb1 null mutants. Strong genetic interactions between Hoxa1 and Hoxb1 were uncovered by introducing the Hoxb1(3′RARE) and Hoxb1 null mutations into the Hoxa1 null genetic background. Hoxa1(null)/Hoxb1(3′RARE) and Hoxa1(null)/Hoxb1(null)double homozygous embryos showed additional patterning defects in the r4-r6 region but maintained a molecularly distinct r4-like territory. Neurofilament staining and retrograde labelling of motor neurons indicated that Hoxa1 and Hoxb1 synergise in patterning the VIIth through XIth cranial nerves. The second arch expression of neural crest cell markers was abolished or dramatically reduced, suggesting a defect in this cell population. Strikingly, the second arch of the double mutant embryos involuted by 10.5 dpc and this resulted in loss of all second arch-derived elements and complete disruption of external and middle ear development. Additional defects, most notably the lack of tympanic ring, were found in first arch-derived elements, suggesting that interactions between first and second arch take place during development. Taken together, our results unveil an extensive functional synergy between Hoxa1 and Hoxb1 that was not anticipated from the phenotypes of the simple null mutants.

Two rhombomeres are altered in Hoxa-1 mutant mice

Development ◽  
1993 ◽  
Vol 119 (2) ◽  
pp. 319-338 ◽  
Author(s):  
M. Mark ◽  
T. Lufkin ◽  
J.L. Vonesch ◽  
E. Ruberte ◽  
J.C. Olivo ◽  
...  
Keyword(s):  
Neural Crest ◽  
Motor Neurons ◽  
Cranial Nerves ◽  
Three Dimensional ◽  
Neural Crest Cell ◽  
Mutant Mice ◽  
Morphological Data ◽  
Vagus Nerves ◽  
Membranous Labyrinth ◽  
Free Region

This study provides a detailed description of the anatomical defects in the Hoxa-1−/− mutant mice previously generated in our laboratory (T. Lufkin, A. Dierich, M. LeMeur, M. Mark and P. Chambon, 1991; Cell 66, 1105–1119). Three-dimensional reconstructions of the Hoxa-1−/− rhombencephalon reveals that it bears only five rhombomeric structures (ie. morphological segments) instead of the normal seven. The first three of these rhombomeres appear normal as judged from the distribution pattern of CRABPI transcripts in the neurectoderm and from the histological analysis of the cranial nerve components derived from these structures. In contrast, the neural-crest-cell-free region normally located opposite rhombomere 5 is lacking in Hoxa-1−/− embryos, and motor neurons of the facial and abducens nerves, which normally differentiate within rhombomeres 4, 5 and 6, are missing in Hoxa-1−/− fetuses. These morphological data, combined with the determination of the molecular positional identities of the rhombomeres 4 and 5 (P. Dolle, T. Lufkin, R. Krumlauf, M. Mark, D. Duboule and P. Chambon, 1993; Proc. Natl. Acad. Sci. USA, in press), suggest that rhombomere 4 is markedly reduced, whereas rhombomere 5 is almost absent. Thus, the remnants of rhombomeres 4 and 5 appear to be fused caudally with rhombomere 6 to form a single fourth rhombomeric structure. Moreover, the migration of neural crest cells contributing to the glossopharyngeal and vagus nerves occurs in a more rostral position, resulting in abnormalities of these cranial nerves, which were visualized by whole-mount anti-neurofilament immunostaining. The mutual relationship along the rostrocaudal axis between the otic pit and the neuroepithelial site of int-2 protein secretion (a putative otogenic cue) is not significantly changed in Hoxa-1−/− embryos. However, the abnormal relationship between the rhombencephalon and the epithelial inner ear may account for the aplasia and faulty differentiation of the membranous labyrinth, the disruption of the cartilaginous otic capsule and the disorganisation of some middle ear structures. This phenotype is compared with that of the Hoxa-1−/− mutants generated by O. Chisaka, T. S. Musci and M. R. Capecchi, 1992 (Nature 335, 516–520) and with that of the mice homozygous for the kreisler mutation.

scholarly journals Msx1 haploinsufficiency modifies the Pax9-deficient cardiovascular phenotype

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ramada R. Khasawneh ◽  
Ralf Kist ◽  
Rachel Queen ◽  
Rafiqul Hussain ◽  
Jonathan Coxhead ◽  
...  
Keyword(s):  
Neural Crest ◽  
Aortic Arch ◽  
Thyroid Cartilage ◽  
Neural Crest Cell ◽  
Pharyngeal Arch ◽  
Palate Development ◽  
The Third ◽  
Pharyngeal Endoderm ◽  
Cardiovascular Defects ◽  
Crest Cell

Abstract Background Successful embryogenesis relies on the coordinated interaction between genes and tissues. The transcription factors Pax9 and Msx1 genetically interact during mouse craniofacial morphogenesis, and mice deficient for either gene display abnormal tooth and palate development. Pax9 is expressed specifically in the pharyngeal endoderm at mid-embryogenesis, and mice deficient for Pax9 on a C57Bl/6 genetic background also have cardiovascular defects affecting the outflow tract and aortic arch arteries giving double-outlet right ventricle, absent common carotid arteries and interruption of the aortic arch. Results In this study we have investigated both the effect of a different genetic background and Msx1 haploinsufficiency on the presentation of the Pax9-deficient cardiovascular phenotype. Compared to mice on a C57Bl/6 background, congenic CD1-Pax9–/– mice displayed a significantly reduced incidence of outflow tract defects but aortic arch defects were unchanged. Pax9–/– mice with Msx1 haploinsufficiency, however, have a reduced incidence of interrupted aortic arch, but more cases with cervical origins of the right subclavian artery and aortic arch, than seen in Pax9–/– mice. This alteration in arch artery defects was accompanied by a rescue in third pharyngeal arch neural crest cell migration and smooth muscle cell coverage of the third pharyngeal arch arteries. Although this change in phenotype could theoretically be compatible with post-natal survival, using tissue-specific inactivation of Pax9 to maintain correct palate development whilst inducing the cardiovascular defects was unable to prevent postnatal death in the mutant mice. Hyoid bone and thyroid cartilage formation were abnormal in Pax9–/– mice. Conclusions Msx1 haploinsufficiency mitigates the arch artery defects in Pax9–/– mice, potentially by maintaining the survival of the 3rd arch artery through unimpaired migration of neural crest cells to the third pharyngeal arches. With the neural crest cell derived hyoid bone and thyroid cartilage also being defective in Pax9–/– mice, we speculate that the pharyngeal endoderm is a key signalling centre that impacts on neural crest cell behaviour highlighting the ability of cells in different tissues to act synergistically or antagonistically during embryo development.

scholarly journals Msx1 Haploinsufficiency Modifies the Pax9-Deficient Cardiovascular Phenotype

2021 ◽  
Author(s):  
Ramada R. Khasawneh ◽  
Ralf Kist ◽  
Jürgen E Schneider ◽  
Timothy J Mohun ◽  
Heiko Peters ◽  
...  
Keyword(s):  
Neural Crest ◽  
Aortic Arch ◽  
Thyroid Cartilage ◽  
Neural Crest Cell ◽  
Pharyngeal Arch ◽  
Palate Development ◽  
The Third ◽  
Pharyngeal Endoderm ◽  
Cardiovascular Defects ◽  
Crest Cell

Abstract Background Successful embryogenesis relies on the coordinated interaction between genes and tissues. The transcription factors Pax9 and Msx1 genetically interact during mouse craniofacial morphogenesis, and mice deficient for either gene display abnormal tooth and palate development. Pax9 is expressed specifically in the pharyngeal endoderm at mid-embryogenesis, and mice deficient for Pax9 on a C57Bl/6 genetic background also have cardiovascular defects affecting the outflow tract and aortic arch arteries giving double-outlet right ventricle, absent common carotid arteries and interruption of the aortic arch. Results In this study we have investigated both the effect of a different genetic background and Msx1 haploinsufficiency on the presentation of the Pax9-deficient cardiovascular phenotype. Compared to mice on a C57Bl/6 background, congenic CD1-Pax9−/− mice displayed a significantly reduced incidence of outflow tract defects but aortic arch defects were unchanged. Pax9−/− mice with Msx1 haploinsufficiency, however, have a reduced incidence of interrupted aortic arch, but more cases with cervical origins of the right subclavian artery and aortic arch, than seen in Pax9−/− mice. This alteration in arch artery defects was accompanied by a rescue in third pharyngeal arch neural crest cell migration and smooth muscle cell coverage of the third pharyngeal arch arteries. Although this change in phenotype could theoretically be compatible with post-natal survival, using tissue-specific inactivation of Pax9 to maintain correct palate development whilst inducing the cardiovascular defects was unable to prevent postnatal death in the mutant mice. Hyoid bone and thyroid cartilage formation were abnormal in Pax9−/− mice. Conclusions Msx1 haploinsufficiency mitigates the arch artery defects in Pax9−/− mice, potentially by maintaining the survival of the 3rd arch artery through unimpaired migration of neural crest cells to the third pharyngeal arches. With the neural crest cell derived hyoid bone and thyroid cartilage also being defective in Pax9−/− mice, we speculate that the pharyngeal endoderm is a key signalling centre that impacts on neural crest cell behaviour highlighting the ability of cells in different tissues to act synergistically or antagonistically during embryo development.

Rhombomere transplantation repatterns the segmental organization of cranial nerves and reveals cell-autonomous expression of a homeodomain protein

Development ◽  
1993 ◽  
Vol 117 (1) ◽  
pp. 105-117 ◽  
Author(s):  
S.C. Kuratani ◽  
G. Eichele
Keyword(s):  
Cell Population ◽  
Nerve Root ◽  
Cranial Nerve ◽  
Hox Genes ◽  
Cranial Nerves ◽  
Neural Crest Cell ◽  
Spinal Nerve ◽  
Homeodomain Protein ◽  
Hox Gene ◽  
Crest Cell

The developing vertebrate hindbrain consists of segmental units known as rhombomeres. Hindbrain neuroectoderm expresses 3′ Hox 1 and 2 cluster genes in characteristic patterns whose anterior limit of expression coincides with rhombomere boundaries. One particular Hox gene, referred to as Ghox 2.9, is initially expressed throughout the hindbrain up to the anterior border of rhombomere 4 (r4). Later, Ghox 2.9 is strongly upregulated in r4 and Ghox 2.9 protein is found in all neuroectodermal cells of r4 and in the hyoid crest cell population derived from this rhombomere. Using a polyclonal antibody, Ghox 2.9 was immunolocalized after transplanting r4 within the hindbrain. Wherever r4 was transplanted, Ghox 2.9 expression was cell-autonomous, both in the neuroectoderm of the graft and in the hyoid crest cell population originating from the graft. In all vertebrates, rhombomeres and cranial nerves (nerves V, VII+VIII, IX, X) exhibit a stereotypic relationship: nerve V arises at the level of r2, nerve VII+VIII at r4 and nerves IX-X extend caudal to r6. To examine how rhombomere transplantation affects this pattern, operated embryos were stained with monoclonal antibodies E/C8 (for visualization of the PNS and of even-numbered rhombomeres) and HNK-1 (to detect crest cells and odd-numbered rhombomeres). Upon transplantation, rhombomeres did not change E/C8 or HNK-1 expression or their ability to produce crest cells. For example, transplanted r4 generated a lateral stream of crest cells irrespective of the site into which it was grafted. Moreover, later in development, ectopic r4 formed an additional cranial nerve root. In contrast, transplantation of r3 (lacks crest cells) into the region of r7 led to inhibition of nerve root formation in the host. These findings emphasize that in contrast to spinal nerve segmentation, which entirely depends on the pattern of somites, cranial nerve patterning is brought about by factors intrinsic to rhombomeres and to the attached neural crest cell populations. The patterns of the neuroectoderm and of the PNS are specified early in hindbrain development and cannot be influenced by tissue transplantation. The observed cell-autonomous expression of Ghox 2.9 (and possibly also of other Hox genes) provides further evidence for the view that Hox gene expression underlies, at least in part, the segmental specification within the hindbrain neuroectoderm.

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