Ectodermal-specific inactivation of Endothelin-1 causes craniofacial developmental defects in mice (original) (raw)
Related papers
Developmental Dynamics, 2012
Background: The basic helix‐loop‐helix (bHLH) transcription factor Twist1 fulfills an essential function in neural crest cell formation, migration, and survival and is associated with the craniosynostic Saethre‐Chotzen syndrome in humans. However, its functions during mandibular development, when it may interact with other bHLH transcription factors like Hand2, are unknown because mice homozygous for the Twist1 null mutation die in early embryogenesis. To determine the role of Twist1 during mandibular development, we used the Hand2‐Cre transgene to conditionally inactivate the gene in the neural crest cells populating the mandibular pharyngeal arch. Results: The mutant mice exhibited a spectrum of craniofacial anomalies, including mandibular hypoplasia, altered middle ear development, and cleft palate. It appears that Twist1 is essential for the survival of the neural crest cells involved in the development of the mandibular ramal elements. Twist1 plays a role in molar development a...
Requirement for Twist1 in frontonasal and skull vault development in the mouse embryo
Developmental Biology, 2009
Using a Cre-mediated conditional deletion approach, we have dissected the function of Twist1 in the morphogenesis of the craniofacial skeleton. Loss of Twist1 in neural crest cells and their derivatives impairs skeletogenic differentiation and leads to the loss of bones of the snout, upper face and skull vault. While no anatomically recognizable maxilla is formed, a malformed mandible is present. Since Twist1 is expressed in the tissues of the maxillary eminence and the mandibular arch, this finding suggests that the requirement for Twist1 is not the same in all neural crest derivatives. The effect of the loss of Twist1 function is not restricted to neural crest-derived bones, since the predominantly mesoderm-derived parietal and interparietal bones are also affected, presumably as a consequence of lost interactions with neural crest-derived tissues. In contrast, the formation of other mesodermal skeletal derivatives such as the occipital bones and most of the chondrocranium are not affected by the loss of Twist1 in the neural crest cells.
Intercellular Genetic Interaction Between Irf6 and Twist1 during Craniofacial Development OPEN
Interferon Regulatory Factor 6 (IRF6) and TWIST1 are transcription factors necessary for craniofacial development. Human genetic studies showed that mutations in IRF6 lead to cleft lip and palate and mandibular abnormalities. In the mouse, we found that loss of Irf6 causes craniosynostosis and mandibular hypoplasia. Similarly, mutations in TWIST1 cause craniosynostosis, mandibular hypoplasia and cleft palate. Based on this phenotypic overlap, we asked if Irf6 and Twist1 interact genetically during craniofacial formation. While single heterozygous mice are normal, double heterozygous embryos (Irf6 +/− ; Twist1 +/−) can have severe mandibular hypoplasia that leads to agnathia and cleft palate at birth. Analysis of spatiotemporal expression showed that Irf6 and Twist1 are found in different cell types. Consistent with the intercellular interaction, we found reduced expression of Endothelin1 (EDN1) in mandible and transcription factors that are critical for mandibular patterning including DLX5, DLX6 and HAND2, were also reduced in mesenchymal cells. Treatment of mandibular explants with exogenous EDN1 peptides partially rescued abnormalities in Meckel's cartilage. In addition, partial rescue was observed when double heterozygous embryos also carried a null allele of p53. Considering that variants in IRF6 and TWIST1 contribute to human craniofacial defects, this gene-gene interaction may have implications on craniofacial disorders. Development of the face is a highly coordinated process that starts after gastrulation with the formation of the frontonasal and pharyngeal arches. The arches are lined by ectoderm superficially and endoderm internally. Cranial neural crest (CNC) cells that may be considered a fourth germ-layer, migrate from the mid-and hind-brain regions into the frontonasal and pharyngeal arches. CNC cells than give rise to many tissues, including bone, cartilage, neuron, ganglia, smooth muscle and odontoblasts 1, 2. In the mandible, CNC and cranial paraxial mesodermal cells contribute to the formation of Meckel's cartilage and the tongue 3–6. Meckel's cartilage provides structural support and biochemical cues for CNC-derived mesenchyme during mandibular development 4, 7. Also, signaling from oral epithelium is critical in regulating proliferation and differentiation of CNC 6, 8. Hence, the development of craniofacial tissues is highly coordinated and interconnected. For example, micrognathia (undersized mandible) can lead to glossoptosis and cleft palate, as seen in patients with Pierre Robin sequence 9, 10. Mandibular disorders are common congenital malformations that can occur as part of genetic syndromes or as an isolated form that can lead to a sequence of anomalies associated with tongue, palate and pharynx 11, 12. The phenotypic expression of mandibular abnormalities ranges from hyperplasia (macrognathia) to hypo-plasia (micrognathia) and to a more severe form characterized by total loss of the mandible (agnathia) 10–12. Micrognathia is the most common mandibular birth defect with a frequency of 1 in 1600 live births 12. Although
Intercellular Genetic Interaction Between Irf6 and Twist1 during Craniofacial Development
Scientific Reports, 2017
Interferon Regulatory Factor 6 (IRF6) and TWIST1 are transcription factors necessary for craniofacial development. Human genetic studies showed that mutations in IRF6 lead to cleft lip and palate and mandibular abnormalities. In the mouse, we found that loss of Irf6 causes craniosynostosis and mandibular hypoplasia. Similarly, mutations in TWIST1 cause craniosynostosis, mandibular hypoplasia and cleft palate. Based on this phenotypic overlap, we asked if Irf6 and Twist1 interact genetically during craniofacial formation. While single heterozygous mice are normal, double heterozygous embryos (Irf6 +/− ; Twist1 +/−) can have severe mandibular hypoplasia that leads to agnathia and cleft palate at birth. Analysis of spatiotemporal expression showed that Irf6 and Twist1 are found in different cell types. Consistent with the intercellular interaction, we found reduced expression of Endothelin1 (EDN1) in mandible and transcription factors that are critical for mandibular patterning including DLX5, DLX6 and HAND2, were also reduced in mesenchymal cells. Treatment of mandibular explants with exogenous EDN1 peptides partially rescued abnormalities in Meckel's cartilage. In addition, partial rescue was observed when double heterozygous embryos also carried a null allele of p53. Considering that variants in IRF6 and TWIST1 contribute to human craniofacial defects, this gene-gene interaction may have implications on craniofacial disorders. Development of the face is a highly coordinated process that starts after gastrulation with the formation of the frontonasal and pharyngeal arches. The arches are lined by ectoderm superficially and endoderm internally. Cranial neural crest (CNC) cells that may be considered a fourth germ-layer, migrate from the mid-and hindbrain regions into the frontonasal and pharyngeal arches. CNC cells than give rise to many tissues, including bone, cartilage, neuron, ganglia, smooth muscle and odontoblasts 1, 2. In the mandible, CNC and cranial paraxial mesodermal cells contribute to the formation of Meckel's cartilage and the tongue 3-6. Meckel's cartilage provides structural support and biochemical cues for CNC-derived mesenchyme during mandibular development 4, 7. Also, signaling from oral epithelium is critical in regulating proliferation and differentiation of CNC 6, 8. Hence, the development of craniofacial tissues is highly coordinated and interconnected. For example, micrognathia (undersized mandible) can lead to glossoptosis and cleft palate, as seen in patients with Pierre Robin sequence 9, 10. Mandibular disorders are common congenital malformations that can occur as part of genetic syndromes or as an isolated form that can lead to a sequence of anomalies associated with tongue, palate and pharynx 11, 12. The phenotypic expression of mandibular abnormalities ranges from hyperplasia (macrognathia) to hypoplasia (micrognathia) and to a more severe form characterized by total loss of the mandible (agnathia) 10-12. Micrognathia is the most common mandibular birth defect with a frequency of 1 in 1600 live births 12. Although
bioRxiv (Cold Spring Harbor Laboratory), 2018
Gnathostome jaws derive from the first pharyngeal arch (PA1), a complex structure constituted by Neural Crest Cells (NCCs), mesodermal, ectodermal and endodermal cells. Here, to determine the regionalized morphogenetic impact of Dlx5/6 expression, we specifically target their inactivation or overexpression to NCCs. NCC-specific Dlx5/6 inactivation (NCC ∆Dlx5/6) generates severely hypomorphic lower jaws that present typical maxillary traits. Therefore, differently from Dlx5/6 null-embryos, the upper and the lower jaws of NCC ∆Dlx5/6 mice present a different size. Reciprocally, forced Dlx5 expression in maxillary NCCs provokes the appearance of distinct mandibular characters in the upper jaw. We conclude that: (1) Dlx5/6 activation in NCCs invariably determines lower jaw identity; (2) the morphogenetic processes that generate functional matching jaws depend on the harmonization of Dlx5/6 expression in NCCs and in distinct ectodermal territories. The co-evolution of synergistic opposing jaws requires the coordination of distinct regulatory pathways involving the same transcription factors in distant embryonic territories.
Disease models & mechanisms, 2012
Bone morphogenetic protein (BMP) receptor type 1A (BMPR1A) mutations are associated with facial dysmorphism, which is one of the main clinical signs in both juvenile polyposis and chromosome 10q23 deletion syndromes. Craniofacial development requires reciprocal epithelial/neural crest (NC)-derived mesenchymal interactions mediated by signaling factors, such as BMP, in both cell populations. To address the role of mesenchymal BMP signaling in craniofacial development, we generated a conditional knockdown mouse by expressing the dominant-negative Bmpr1a in NC-derived cells expressing the myelin protein zero(Mpz)-Cre transgene. At birth, 100% of the conditional mutant mice had wide-open anterior fontanelles, and 80% of them died because of cleft face and cleft palate soon after birth. The other 20% survived and developed short faces, hypertelorism and calvarial foramina. Analysis of the NC-derived craniofacial mesenchyme of mutant embryos revealed an activation of the P53 apoptosis pat...
Developmental Biology, 2012
Morphogenesis of the vertebrate head relies on proper dorsal-ventral (D-V) patterning of neural crest cells (NCC) within the pharyngeal arches. Endothelin-1 (Edn1)-induced signaling through the endothelin-A receptor (Ednra) is crucial for cranial NCC patterning within the mandibular portion of the first pharyngeal arch, from which the lower jaw arises. Deletion of Edn1, Ednra or endothelinconverting enzyme in mice causes perinatal lethality due to severe craniofacial birth defects. These include homeotic transformation of mandibular arch-derived structures into more maxillary-like structures, indicating a loss of NCC identity. All cranial NCCs express Ednra whereas Edn1 expression is limited to the overlying ectoderm, core paraxial mesoderm and pharyngeal pouch endoderm of the mandibular arch as well as more caudal arches. To define the developmental significance of Edn1 from each of these layers, we used Cre/loxP technology to inactivate Edn1 in a tissue-specific manner. We show that deletion of Edn1 in either the mesoderm or endoderm alone does not result in cellular or molecular changes in craniofacial development. However, ectodermal deletion of Edn1 results in craniofacial defects with concomitant changes in the expression of early mandibular arch patterning genes. Importantly, our results also both define for the first time in mice an intermediate mandibular arch domain similar to the one defined in zebrafish and show that this region is most sensitive to loss of Edn1. Together, our results illustrate an integral role for ectoderm-derived Edn1 in early arch morphogenesis, particularly in the intermediate domain.
Molecular Mechanism of Cranial Neural Crest Cell Development
The craniofacial region, comprising the face and the skull, is largely the product of cranial neural crest (CNC) cells, in which CNC cells form most of the bone, cartilage and connective tissues. Genetic mutations, environmental factors, and nutritional deficiencies have been identified as risk factors to affect the fate of CNC cells and cause craniofacial deformities. Many signaling pathways and their interactions are involved in the formation of CNC derivatives and disturbances of these cascades are attributed as etiological agents for craniofacial pathologies. Much progress has been made in identifying causative factors associated with craniofacial anomalies; however, the etiologies of craniofacial birth defects are still largely unknown. In this review, we focus on the current understanding of the molecular networks involved in the fate determination of CNC cells during craniofacial development.
Negative regulation of Endothelin signaling by SIX1 is required for proper maxillary development
Development (Cambridge, England), 2017
Jaw morphogenesis is a complex event mediated by inductive signals that establish and maintain the distinct developmental domains required for formation of hinged jaws, the defining feature of gnathostomes. The mandibular portion of pharyngeal arch one is patterned dorsally by JAGGED-NOTCH signaling and ventrally by Endothelin receptor-A (EDNRA) signaling. Loss of EDNRA signaling disrupts normal ventral gene expression, the result of which is homeotic transformation of the mandible into a maxilla-like structure. However, loss of JAGGED-NOTCH signaling does not result in significant changes in maxillary development. Here we show that the transcription factor SIX1 regulates dorsal arch development not only by inducing dorsal Jag1 expression but also by inhibiting Endothelin1 (Edn1) expression in the pharyngeal endoderm of the dorsal arch, thus preventing dorsal EDNRA signaling. In the absence of SIX1, but not JAG1, aberrant EDNRA signaling in the dorsal domain results in partial dupli...
The role of neural crest cells and homeobox genes in craniofacial development
2010
The role of neural crest cells in the development of craniofacial development has been a topic of research for the molecular biologist for decades. With the discovery of the homeobox genes, many research and investigations have shown that there is a genetic control for the patterning of the craniofacial region. With the identifi cation of more different types of homeobox gene along with the transcription factors, it is becoming clearer that the homeobox genes have greater role than previously thought. With advancement of the research techniques, more insights of the role of these genes have been explored. These genes in fact are found to be the regulators and thus the master genes of the head and face. So it is now transparent that there is a genetic domination over the development and the patterning of the head and facial region through these genes. This review article tends to give a simplifi ed overview of the role of neural crest cells and homeobox genes in the development of the craniofacial complex.