A signaling cascade involving endothelin-1, dHAND and msx1 regulates development of neural-crest-derived branchial arch mesenchyme

Development ◽  
1998 ◽  
Vol 125 (16) ◽  
pp. 3005-3014 ◽  
Author(s):  
T. Thomas ◽  
H. Kurihara ◽  
H. Yamagishi ◽  
Y. Kurihara ◽  
Y. Yazaki ◽  
...  
Keyword(s):  
Neural Crest ◽  
Regulatory Elements ◽  
Branchial Arch ◽  
Limb Bud ◽  
Abnormal Development ◽  
Cardiac Defects ◽  
Endothelin 1 ◽  
The Third ◽  
Branchial Arches ◽  
Catch 22

Numerous human syndromes are the result of abnormal cranial neural crest development. One group of such defects, referred to as CATCH-22 (cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, hypocalcemia, associated with chromosome 22 microdeletion) syndrome, exhibit craniofacial and cardiac defects resulting from abnormal development of the third and fourth neural crest-derived branchial arches and branchial arch arteries. Mice harboring a null mutation of the endothelin-1 gene (Edn1), which is expressed in the epithelial layer of the branchial arches and encodes for the endothelin-1 (ET-1) signaling peptide, have a phenotype similar to CATCH-22 syndrome with aortic arch defects and craniofacial abnormalities. Here we show that the basic helix-loop-helix transcription factor, dHAND, is expressed in the mesenchyme underlying the branchial arch epithelium. Further, dHAND and the related gene, eHAND, are downregulated in the branchial and aortic arches of Edn1-null embryos. In mice homozygous null for the dHAND gene, the first and second arches are hypoplastic secondary to programmed cell death and the third and fourth arches fail to form. Molecular analysis revealed that most markers of the neural-crest-derived components of the branchial arch are expressed in dHAND-null embryos, suggesting normal migration of neural crest cells. However, expression of the homeobox gene, Msx1, was undetectable in the mesenchyme of dHAND-null branchial arches but unaffected in the limb bud, consistent with the separable regulatory elements of Msx1 previously described. Together, these data suggest a model in which epithelial secretion of ET-1 stimulates mesenchymal expression of dHAND, which regulates Msx1 expression in the growing, distal branchial arch. Complete disruption of this molecular pathway results in growth failure of the branchial arches from apoptosis, while partial disruption leads to defects of branchial arch derivatives, similar to those seen in CATCH-22 syndrome.

scholarly journals Cooperative Action of Multiple cis-Acting Elements Is Required for N-myc Expression in Branchial Arches: Specific Contribution of GATA3

2010 ◽  
Vol 30 (22) ◽  
pp. 5348-5363 ◽  
Author(s):  
Éric Potvin ◽  
Laurent Beuret ◽  
Jean-François Cadrin-Girard ◽  
Marcelle Carter ◽  
Sophie Roy ◽  
...  
Keyword(s):  
Regulatory Element ◽  
Regulatory Elements ◽  
Branchial Arch ◽  
Tumor Formation ◽  
Limb Bud ◽  
Developmental Expression ◽  
Limb Buds ◽  
Cooperative Action ◽  
First Intron ◽  
Branchial Arches

ABSTRACT The precise expression of the N-myc proto-oncogene is essential for normal mammalian development, whereas altered N-myc gene regulation is known to be a determinant factor in tumor formation. Using transgenic mouse embryos, we show that N-myc sequences from kb −8.7 to kb +7.2 are sufficient to reproduce the N-myc embryonic expression profile in developing branchial arches and limb buds. These sequences encompass several regulatory elements dispersed throughout the N-myc locus, including an upstream limb bud enhancer, a downstream somite enhancer, a branchial arch enhancer in the second intron, and a negative regulatory element in the first intron. N-myc expression in the limb buds is under the dominant control of the limb bud enhancer. The expression in the branchial arches necessitates the interplay of three regulatory domains. The branchial arch enhancer cooperates with the somite enhancer region to prevent an inhibitory activity contained in the first intron. The characterization of the branchial arch enhancer has revealed a specific role of the transcription factor GATA3 in the regulation of N-myc expression. Together, these data demonstrate that correct N-myc developmental expression is achieved via cooperation of multiple positive and negative regulatory elements.

Jaw and branchial arch mutants in zebrafish I: branchial arches

Development ◽  
1996 ◽  
Vol 123 (1) ◽  
pp. 329-344 ◽  
Author(s):  
T.F. Schilling ◽  
T. Piotrowski ◽  
H. Grandel ◽  
M. Brand ◽  
C.P. Heisenberg ◽  
...  
Keyword(s):  
Neural Crest ◽  
Zebrafish Embryo ◽  
Neural Crest Cells ◽  
Branchial Arch ◽  
Pigment Cells ◽  
Pharyngeal Arches ◽  
Pectoral Fins ◽  
Branchial Arches ◽  
Group Members ◽  
The Brain

Jaws and branchial arches together are a basic, segmented feature of the vertebrate head. Seven arches develop in the zebrafish embryo (Danio rerio), derived largely from neural crest cells that form the cartilaginous skeleton. In this and the following paper we describe the phenotypes of 109 arch mutants, focusing here on three classes that affect the posterior pharyngeal arches, including the hyoid and five gill-bearing arches. In lockjaw, the hyoid arch is strongly reduced and subsets of branchial arches do not develop. Mutants of a large second class, designated the flathead group, lack several adjacent branchial arches and their associated cartilages. Five alleles at the flathead locus all lead to larvae that lack arches 4–6. Among 34 other flathead group members complementation tests are incomplete, but at least six unique phenotypes can be distinguished. These all delete continuous stretches of adjacent branchial arches and unpaired cartilages in the ventral midline. Many show cell death in the midbrain, from which some neural crest precursors of the arches originate. lockjaw and a few mutants in the flathead group, including pistachio, affect both jaw cartilage and pigmentation, reflecting essential functions of these genes in at least two neural crest lineages. Mutants of a third class, including boxer, dackel and pincher, affect pectoral fins and axonal trajectories in the brain, as well as the arches. Their skeletal phenotypes suggest that they disrupt cartilage morphogenesis in all arches. Our results suggest that there are sets of genes that: (1) specify neural crest cells in groups of adjacent head segments, and (2) function in common genetic pathways in a variety of tissues including the brain, pectoral fins and pigment cells as well as pharyngeal arches.

Fgf-8 determines rostral-caudal polarity in the first branchial arch

Development ◽  
1999 ◽  
Vol 126 (1) ◽  
pp. 51-61 ◽  
Author(s):  
A.S. Tucker ◽  
G. Yamada ◽  
M. Grigoriou ◽  
V. Pachnis ◽  
P.T. Sharpe
Keyword(s):  
Neural Crest ◽  
Branchial Arch ◽  
Cell Fates ◽  
Spatial Expression ◽  
Mandibular Arch ◽  
Endothelin 1 ◽  
Lower Jaw ◽  
Cell Competence ◽  
Mesenchyme Cells

In mammals, rostral ectomesenchyme cells of the mandibular arch give rise to odontogenic cells, while more caudal cells form the distal skeletal elements of the lower jaw. Signals from the epithelium are required for the development of odontogenic and skeletogenic mesenchyme cells. We show that rostral-caudal polarity is first established in mandibular branchial arch ectomesenchymal cells by a signal, Fgf-8, from the rostral epithelium. All neural crest-derived ectomesenchymal cells are equicompetent to respond to Fgf-8. The restriction into rostral (Lhx-7-expressing) and caudal (Gsc-expressing) domains is achieved by cells responding differently according to their proximity to the source of the signal. Once established, spatial expression domains and cell fates are fixed and maintained by Fgf-8 in conjunction with another epithelial signal, endothelin-1, and by positional changes in ectomesenchymal cell competence to respond to the signal.

scholarly journals Transcriptome profiling of the branchial arches reveals cell type composition and a conserved signature of neural crest cell invasion

2020 ◽  
Author(s):  
Jason A Morrison ◽  
Rebecca McLennan ◽  
Jessica M Teddy ◽  
Allison R Scott ◽  
Jennifer C Kasemeier-Kulesa ◽  
...  
Keyword(s):  
Neural Crest ◽  
Cell Invasion ◽  
Neural Crest Cell ◽  
Branchial Arch ◽  
Tissue Growth ◽  
Cell Populations ◽  
Label Free ◽  
Cell Type ◽  
Mesoderm Cell ◽  
Branchial Arches

ABSTRACTThe vertebrate branchial arches that give rise to structures of the head, neck, and heart form with very dynamic tissue growth and well-choreographed neural crest, ectoderm, and mesoderm cell dynamics. Although this morphogenesis has been studied by marker expression and fate-mapping, the mechanisms that control the collective migration and diversity of the neural crest and surrounding tissues remain unclear, in part due to the effects of averaging and need for cell isolation in conventional transcriptome analysis experiments of multiple cell populations. We used label free single cell RNA sequencing on 95,000 individual cells at 2 developmental stages encompassing formation of the first four chick branchial arches to measure the transcriptional states that define the cellular hierarchy and invasion signature of the migrating neural crest. The results confirmed basic features of cell type diversity and led to the discovery of many novel markers that discriminate between axial level and distal-to-proximal cell populations within the branchial arches and neural crest streams. We identified the transcriptional signature of the most invasive neural crest that is conserved within each branchial arch stream and elucidated a set of genes common to other cell invasion signatures in types in cancer, wound healing and development. These data robustly delineate molecularly distinct cell types within the branchial arches and identify important molecular transitions within the migrating neural crest during development.

scholarly journals Dorsal hindbrain ablation results in rerouting of neural crest migration and changes in gene expression, but normal hyoid development

Development ◽  
1997 ◽  
Vol 124 (14) ◽  
pp. 2729-2739 ◽  
Author(s):  
J.R. Saldivar ◽  
J.W. Sechrist ◽  
C.E. Krull ◽  
S. Ruffins ◽  
M. Bronner-Fraser
Keyword(s):  
Gene Expression ◽  
Neural Crest ◽  
Neural Tube ◽  
Neural Crest Cells ◽  
Branchial Arch ◽  
Surgical Ablation ◽  
The Third ◽  
Somite Stage ◽  
Or Gene ◽  
Dorsal Hindbrain

Our previous studies have shown that hindbrain neural tube cells can regulate to form neural crest cells for a limited time after neural fold removal (Scherson, T., Serbedzija, G., Fraser, S. E. and Bronner-Fraser, M. (1993). Development 188, 1049–1061; Sechrist, J., Nieto, M. A., Zamanian, R. T. and Bronner-Fraser, M. (1995). Development 121, 4103–4115). In the present study, we ablated the dorsal hindbrain at later stages to examine possible alterations in migratory behavior and/or gene expression in neural crest populations rostral and caudal to the operated region. The results were compared with those obtained by misdirecting neural crest cells via rhombomere rotation. Following surgical ablation of dorsal r5 and r6 prior to the 10 somite stage, r4 neural crest cells migrate along normal pathways toward the second branchial arch. Similarly, r7 neural crest cells migrate primarily to the fourth branchial arch. When analogous ablations are performed at the 10–12 somite stage, however, a marked increase in the numbers of DiI/Hoxa-3-positive cells from r7 are observed within the third branchial arch. In addition, some DiI-labeled r4 cells migrate into the depleted hindbrain region and the third branchial arch. During their migration, a subset of these r4 cells up-regulate Hoxa-3, a transcript they do not normally express. Krox20 transcript levels were augmented after ablation in a population of neural crest cells migrating from r4, caudal r3 and rostral r3. Long-term survivors of bilateral ablations possess normal neural crest-derived cartilage of the hyoid complex, suggesting that misrouted r4 and r7 cells contribute to cranial derivatives appropriate for their new location. In contrast, misdirecting of the neural crest by rostrocaudal rotation of r4 through r6 results in a reduction of Hoxa-3 expression in the third branchial arch and corresponding deficits in third arch-derived structures of the hyoid apparatus. These results demonstrate that neural crest/tube progenitors in the hindbrain can compensate by altering migratory trajectories and patterns of gene expression when the adjacent neural crest is removed, but fail to compensate appropriately when the existing neural crest is misrouted by neural tube rotation.

scholarly journals Rhombomere rotation reveals that multiple mechanisms contribute to the segmental pattern of hindbrain neural crest migration

Development ◽  
1994 ◽  
Vol 120 (7) ◽  
pp. 1777-1790 ◽  
Author(s):  
J. Sechrist ◽  
T. Scherson ◽  
M. Bronner-Fraser
Keyword(s):  
Neural Crest ◽  
Neural Tube ◽  
Neural Crest Cells ◽  
Branchial Arch ◽  
Otic Vesicle ◽  
Branchial Arches ◽  
Migratory Pattern ◽  
Neural Crest Migration ◽  
Surgical Manipulation ◽  
Otic Vesicles

Hindbrain neural crest cells adjacent to rhombomeres 2 (r2), r4 and r6 migrate in a segmental pattern, toward the first, second and third branchial arches, respectively. Although all rhombomeres generate neural crest cells, those arising from r3 and r5 deviate rostrally and caudally (J. Sechrist, G. Serbedzija, T. Scherson, S. Fraser and M. Bronner-Fraser (1993) Development 118, 691–703). We have altered the rostrocaudal positions of the cranial neural tube, adjacent ectoderm/mesoderm or presumptive otic vesicle to examine tissue influences on this segmental migratory pattern. After neural tube rotation, labeled neural crest cells follow pathways generally appropriate for their new position after grafting. For example, when r3 and r4 were transposed, labeled r3 cells migrated laterally to the second branchial arch whereas labeled r4 cells primarily deviated caudally toward the second arch, with some cells moving rostrally toward the first. In contrast to r4 neural crest cells, transposed r3 cells leave the neural tube surface in a polarized manner, near the r3/4 border. Surprisingly, some labeled neural crest cells moved directionally toward small ectopic otic vesicles that often formed in the ectoderm adjacent to grafted r4. Similarly, they moved toward grafted or displaced otic vesicles. In contrast, surgical manipulation of the mesoderm adjacent to r3 and r4 had no apparent effects. Our results offer evidence that neural crest cells migrate directionally toward the otic vesicle, either by selective attraction or pathway-derived cues.

scholarly journals Rare dosage abnormalities flanking the SHOX gene

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
David J. Bunyan ◽  
Evelien Gevers ◽  
James I. Hobbs ◽  
Philippa J. Duncan-Flavell ◽  
Rachel J. Howarth ◽  
...  
Keyword(s):  
Copy Number ◽  
Regulatory Element ◽  
Copy Number Variants ◽  
Regulatory Elements ◽  
Limb Bud ◽  
Shox Gene ◽  
Coding Sequences ◽  
The Third ◽  
Copy Number Changes

Abstract Background Transcriptional regulation of the SHOX gene is highly complex. Much of our understanding has come from the study of copy number changes of conserved non-coding sequences both upstream and downstream of the gene. Downstream deletions have been frequently reported in patients with Leri–Weill dyschondrosteosis or idiopathic short stature. In contrast, there are only four cases in the literature of upstream deletions that remove regulatory elements. Although duplications flanking the SHOX gene have also been reported, their pathogenicity is more difficult to establish. To further evaluate the role of flanking copy number variants in SHOX-related disorders, we describe nine additional patients from a large SHOX diagnostic cohort. Results The nine cases presented here include five with duplications (two upstream of SHOX and three downstream), one with a downstream triplication and three with upstream deletions. Two of the deletions remove a single conserved non-coding element (CNE-3) while the third does not remove any known regulatory element but is just 4 kb upstream of SHOX, and the deleted region may be important in limb bud development. We also describe six families with novel sequence gains flanking SHOX. Three families had increased dosage of a proposed regulatory element approximately 380 kb downstream of SHOX (X:970,000), including one family with the first ever reported triplication of this region. One family had two in cis downstream duplications co-segregating with LWD, and the two others had a duplication of just the upstream SHOX regulatory element CNE-5. Conclusions This study further extends our knowledge of the range of variants that may potentially cause SHOX-related phenotypes and may aid in determining the clinical significance of similar variants.

Spatial organization of the epithelium and the role of neural crest cells in the initiation of the mammalian tooth germ

Development ◽  
1988 ◽  
Vol 103 (Supplement) ◽  
pp. 155-169 ◽  
Author(s):  
A. G. S. Lumsden
Keyword(s):  
Neural Crest ◽  
Spatial Organization ◽  
Developmental Stages ◽  
Neural Crest Cells ◽  
Branchial Arch ◽  
Limb Bud ◽  
Oral Epithelium ◽  
Cranial Neural Crest ◽  
Surface Ectoderm ◽  
Mandibular Arch

Teeth develop from composite organ rudiments that are formed through the interaction of oral epithelium and mesenchyme of the first branchial arch; cells of the former differentiate into enamel-secreting ameloblasts whereas those of the latter differentiate into dentine-secreting odontoblasts. Experimental analysis of odontogenic tissue interactions in mammalian embryos has focused on the late developmental stages of morphogenesis and cytodifferentiation; little is known about initial pattern-forming events, during which presumptive tooth-forming cells are specified and the sites of tooth initiation become established. It requires to be shown, for example, whether the mesenchymal cells of mammalian teeth are derived, like those of amphibians, from the cranial neural crest, and if so, whether these form a specified subpopulation in the neural folds. Alternatively, are they specified after migration into the mandibular arch, possibly by interaction with the oral epithelium? The developmental potentials of mouse embryo premigratory cranial neural crest cells (CNC – explanted from the caudal mesencephalic and rostral metencephalic neural folds) have been studied in intraocular homograft recombinations with various regions of embryonic surface ectoderm. Cartilage, bone and neural tissue developed in all combinations of CNC and epithelium. Teeth formed in combinations of CNC with mandibular arch epithelium but not in combinations of CNC with limb bud epithelium. Teeth also formed in combinations of mandibular arch epithelium with neural crest explanted from the trunk level. These results indicate that mammalian neural crest has an odontogenic potential but that this is not restricted to the crest of presumptive tooth-forming levels. Normal migration appears not to be a prerequisite for expression of odontogenic potential but this does require an interaction with region-specific epithelium. It is reasonable to infer that during normal development the neural crest that enters the mandibular arch is odontogenically unspecified before or during migration and that the oral epithelium is the earliest known site of tooth pattern.

Homeotic transformation of branchial arch identity after Hoxa2 overexpression

Development ◽  
2000 ◽  
Vol 127 (24) ◽  
pp. 5355-5365 ◽  
Author(s):  
G.A. Grammatopoulos ◽  
E. Bell ◽  
L. Toole ◽  
A. Lumsden ◽  
A.S. Tucker
Keyword(s):  
Neural Crest ◽  
Branchial Arch ◽  
Reverse Transformation ◽  
Surrounding Tissue ◽  
Homeotic Transformation ◽  
Branchial Arches ◽  
Arch Neural

Overexpression of Hoxa2 in the chick first branchial arch leads to a transformation of first arch cartilages, such as Meckel's and the quadrate, into second arch elements, such as the tongue skeleton. These duplicated elements are fused to the original in a similar manner to that seen in the Hoxa2 knockout, where the reverse transformation of second to first arch morphology is observed. This confirms the role of Hoxa2 as a selector gene specifying second arch fate. When first arch neural crest alone is targeted, first arch elements are lost, but the Hoxa2-expressing crest is unable to develop into second arch elements. This is not due to Hoxa2 preventing differentiation of cartilages. Upregulation of a second arch marker in the first arch, and homeotic transformation of cartilage elements is only produced after global Hoxa2 overexpression in the crest and the surrounding tissue. Thus, although the neural crest appears to contain some patterning information, it needs to read cues from the environment to form a coordinated pattern. Hoxa2 appears to exert its effect during differentiation of the cartilage elements in the branchial arches, rather than during crest migration, implying that pattern is determined quite late in development.

scholarly journals Pharmacological inactivation of the endothelin type A receptor in the early chick embryo: a model of mispatterning of the branchial arch derivatives

Development ◽  
1998 ◽  
Vol 125 (24) ◽  
pp. 4931-4941 ◽  
Author(s):  
H. Kempf ◽  
C. Linares ◽  
P. Corvol ◽  
J.M. Gasc
Keyword(s):  
Chick Embryo ◽  
Neural Crest ◽  
Type A ◽  
Branchial Arch ◽  
In Ovo ◽  
Time Of Application ◽  
Branchial Arches ◽  
Eta Receptor ◽  
Temporal Expression Pattern ◽  
High Level

In the present study, we have applied an antagonist treatment to the chick embryo in ovo in order to demonstrate and dissect the essential roles of the endothelin type A (ETA) receptor in the embryonic development. We have cloned, sequenced and expressed the cDNA of the chick ETA receptor and shown that its affinity for endothelin antagonists is very similar to that shown by its mammalian counterparts. We have studied the spatio-temporal expression pattern of this receptor by in situ hybridization and shown that there is a high level of its mRNA within the mesenchyme of the branchial arches at E3-E5, in keeping with the direct effect of endothelin-1 (ET-1) on the fate of this region of the embryo. Unlike the endothelin type B (ETB) receptor mRNA, ETA mRNA is not expressed in neural crest cells during emigration from the neural tube, but is detected in neural crest-derived ectomesenchyme of the branchial arches. Finally, the functional involvement of this receptor in craniofacial and cardiovascular organogenesis was assessed by selectively inactivating the ETA receptor with specific antagonists applied during the time period corresponding to the expression of the ETA receptor and colonisation of the branchial arches. Embryos treated by these antagonists show a severe reduction and dysmorphogenesis of the hypobranchial skeleton, as well as heart and aortic arch derivative defects. This phenotype is very similar to that obtained in mice by gene inactivations of ET-1 and ETA. These results are observed with ETA antagonists but not with an ETB antagonist, and are dependent on the dose of the antagonists used and on the time of application to the embryo. Altogether, these data strongly show that the ET-1/ETA pathway, in chicken as in mammals, is a major factor involved directly and functionally in morphogenesis of the face and heart. This experimental model of pharmacological inactivation of a gene product described in this study offers a simple and rapid alternative to gene inactivation in mouse. This strategy can be applied to other ligand-receptor systems and extended to compounds of various chemical and functional natures.

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