Independent regulation of Dlx2 expression in the epithelium and mesenchyme of the first branchial arch

Development ◽  
2000 ◽  
Vol 127 (2) ◽  
pp. 217-224 ◽  
Author(s):  
B.L. Thomas ◽  
J.K. Liu ◽  
J.L. Rubenstein ◽  
P.T. Sharpe
Keyword(s):  
Tooth Development ◽  
Branchial Arch ◽  
Oral Epithelium ◽  
Upstream Sequence ◽  
Loss Of Function ◽  
Signalling Molecules ◽  
Molar Teeth ◽  
Overlapping Domains ◽  
Upper Molar

Dlx2, a member of the distal-less gene family, is expressed in the first branchial arch, prior to the initiation of tooth development, in distinct, non-overlapping domains in the mesenchyme and the epithelium. In the mesenchyme Dlx2 is expressed proximally, whereas in oral epithelium it is expressed distally. Dlx2 has been shown to be involved in the patterning of the murine dentition, since loss of function of Dlx1 and Dlx2 results in early failure of development of upper molar teeth. We have investigated the regulation of Dlx2 expression to determine how the early epithelial and mesenchymal expression boundaries are maintained, to help to understand the role of these distinct expression domains in patterning of the dentition. Transgenic mice produced with a lacZ reporter construct, containing 3.8 kb upstream sequence of Dlx2, led to the mapping of regulatory regions driving epithelial but not mesenchymal expression in the first branchial arch. We show that the epithelial expression of Dlx2 is regulated by planar signalling by BMP4, which is coexpressed in distal oral epithelium. Mesenchymal expression is regulated by a different mechanism involving FGF8, which is expressed in the overlying epithelium. FGF8 also inhibits expression of Dlx2 in the epithelium by a signalling pathway that requires the mesenchyme. Thus, the signalling molecules BMP4 and FGF8 provide the mechanism for maintaining the strict epithelial and mesenchymal expression domains of Dlx2 in the first arch.

Role of Dlx-1 and Dlx-2 genes in patterning of the murine dentition

Development ◽  
1997 ◽  
Vol 124 (23) ◽  
pp. 4811-4818 ◽  
Author(s):  
B.L. Thomas ◽  
A.S. Tucker ◽  
M. Qui ◽  
C.A. Ferguson ◽  
Z. Hardcastle ◽  
...  
Keyword(s):  
Neural Crest ◽  
Homeobox Gene ◽  
Branchial Arch ◽  
Cranial Neural Crest ◽  
Loss Of Function ◽  
Molecular Events ◽  
Maxillary Molar ◽  
Molar Teeth ◽  
Cranial Neural Crest Cells ◽  
Arch Neural

The molecular events of odontogenic induction are beginning to be elucidated, but until now nothing was known about the molecular basis of the patterning of the dentition. A role for Dlx-1 and Dlx-2 genes in patterning of the dentition has been proposed with the genes envisaged as participating in an ‘odontogenic homeobox gene code’ by specifying molar development. This proposal was based on the restricted expression of the genes in molar ectomesenchyme derived from cranial neural crest cells prior to tooth initiation. Mice with targeted null mutations of both Dlx-1 and Dlx-2 homeobox genes do not develop maxillary molar teeth but incisors and mandibular molars are normal. We have carried out heterologous recombinations between mutant and wild-type maxillary epithelium and mesenchyme and show that the ectomesenchyme underlying the maxillary molar epithelium has lost its odontogenic potential. Using molecular markers of branchial arch neural crest (Barx1) and commitment to chondrogenic differentiation (Sox9), we show that this population alters its fate from odontogenic to become chondrogenic. These results provide evidence that a subpopulation of cranial neural crest is specified as odontogenic by Dlx-1 and Dlx-2 genes. Loss of function of these genes results in reprogramming of this population of ectomesenchyme cells into chondrocytes. This is the first indication that the development of different shaped teeth at different positions in the jaws is determined by independent genetic pathways.

Inhibition of Apoptosis in Early Tooth Development Alters Tooth Shape and Size

2006 ◽  
Vol 85 (6) ◽  
pp. 530-535 ◽  
Author(s):  
J.-Y. Kim ◽  
Y.-G. Cha ◽  
S.-W. Cho ◽  
E.-J. Kim ◽  
M.-J. Lee ◽  
...  
Keyword(s):  
Tooth Development ◽  
Tooth Germ ◽  
Dependent Manner ◽  
Crown Height ◽  
Concentration Dependent Manner ◽  
Molar Teeth ◽  
In Vitro Organ Culture ◽  
Shape And Size

Apoptosis plays important roles in various stages of organogenesis. In this study, we hypothesized that apoptosis would play an important role in tooth morphogenesis. We examined the role of apoptosis in early tooth development by using a caspase inhibitor, z-VAD-fmk, concomitant with in vitro organ culture and tooth germ transplantation into the kidney capsule. Inhibition of apoptosis at the early cap stage did not disrupt the cell proliferation level when compared with controls. However, the macroscopic morphology of mice molar teeth exhibited dramatic alterations after the inhibition of apoptosis. Crown height was reduced, and mesiodistal diameter was increased in a concentration-dependent manner with z-VAD-fmk treatment. Overall, apoptosis in the enamel knot would be necessary for the proper formation of molar teeth, including appropriate shape and size.

Sonic hedgehog regulates growth and morphogenesis of the tooth

Development ◽  
2000 ◽  
Vol 127 (22) ◽  
pp. 4775-4785 ◽  
Author(s):  
H.R. Dassule ◽  
P. Lewis ◽  
M. Bei ◽  
R. Maas ◽  
A.P. McMahon
Keyword(s):  
Sonic Hedgehog ◽  
Tooth Development ◽  
Oral Epithelium ◽  
Signaling Proteins ◽  
Conditional Allele ◽  
Oral Ectoderm ◽  
In The Wild ◽  
Crown Formation ◽  
Dental Epithelium

During mammalian tooth development, the oral ectoderm and mesenchyme coordinate their growth and differentiation to give rise to organs with precise shapes, sizes and functions. The initial ingrowth of the dental epithelium and its associated dental mesenchyme gives rise to the tooth bud. Next, the epithelial component folds to give the tooth its shape. Coincident with this process, adjacent epithelial and mesenchymal cells differentiate into enamel-secreting ameloblasts and dentin-secreting odontoblasts, respectively. Growth, morphogenesis and differentiation of the epithelium and mesenchyme are coordinated by secreted signaling proteins. Sonic hedgehog (Shh) encodes a signaling peptide which is present in the oral epithelium prior to invagination and in the tooth epithelium throughout its development. We have addressed the role of Shh in the developing tooth in mouse by using a conditional allele to remove Shh activity shortly after ingrowth of the dental epithelium. Reduction and then loss of Shh function results in a cap stage tooth rudiment in which the morphology is severely disrupted. The overall size of the tooth is reduced and both the lingual epithelial invagination and the dental cord are absent. However, the enamel knot, a putative organizer of crown formation, is present and expresses Fgf4, Wnt10b, Bmp2 and Lef1, as in the wild type. At birth, the size and the shape of the teeth are severely affected and the polarity and organization of the ameloblast and odontoblast layers is disrupted. However, both dentin- and enamel-specific markers are expressed and a large amount of tooth-specific extracellular matrix is produced. This observation was confirmed by grafting studies in which tooth rudiments were cultured for several days under kidney capsules. Under these conditions, both enamel and dentin were deposited even though the enamel and dentin layers remained disorganized. These studies demonstrate that Shh regulates growth and determines the shape of the tooth. However, Shh signaling is not essential for differentiation of ameloblasts or odontoblasts.

scholarly journals The genetic basis of modularity in the development and evolution of the vertebrate dentition

2001 ◽  
Vol 356 (1414) ◽  
pp. 1633-1653 ◽  
Author(s):  
David W. Stock
Keyword(s):  
Genetic Control ◽  
Tooth Loss ◽  
Tooth Development ◽  
Ectopic Expression ◽  
Small Subset ◽  
Oral Epithelium ◽  
Specific Expression ◽  
Tooth Shape ◽  
Signalling Molecules ◽  
Tooth Type

The construction of organisms from units that develop under semi–autonomous genetic control (modules) has been proposed to be an important component of their ability to undergo adaptive phenotypic evolution. The organization of the vertebrate dentition as a system of repeated parts provides an opportunity to study the extent to which phenotypic modules, identified by their evolutionary independence from other such units, are related to modularity in the genetic control of development. The evolutionary history of vertebrates provides numerous examples of both correlated and independent evolution of groups of teeth. The dentition itself appears to be a module of the dermal exoskeleton, from which it has long been under independent genetic control. Region–specific tooth loss has been a common trend in vertebrate evolution. Novel deployment of teeth and reacquisition of lost teeth have also occurred, although less frequently. Tooth shape differences within the dentition may be discontinuous (referred to as heterodonty) or graded. The occurrence of homeotic changes in tooth shape provides evidence for the decoupling of tooth shape and location in the course of evolution. Potential mechanisms for region–specific evolutionary tooth loss are suggested by a number of mouse gene knockouts and human genetic dental anomalies, as well as a comparison between fully–developed and rudimentary teeth in the dentition of rodents. These mechanisms include loss of a tooth–type–specific initiation signal, alterations of the relative strength of inductive and inhibitory signals acting at the time of tooth initiation and the overall reduction in levels of proteins required for the development of all teeth. Ectopic expression of tooth initiation signals provides a potential mechanism for the novel deployment or reacquisition of teeth; a single instance is known of a gene whose ectopic expression in transgenic mice can lead to ectopic teeth. Differences in shape between incisor and molar teeth in the mouse have been proposed to be controlled by the region–specific expression of signalling molecules in the oral epithelium. These molecules induce the expression of transcription factors in the underlying jaw mesenchyme that may act as selectors of tooth type. It is speculated that shifts in the expression domains of the epithelial signalling molecules might be responsible for homeotic changes in tooth shape. The observation that these molecules are regionally restricted in the chicken, whose ancestors were not heterodont, suggests that mammalian heterodonty may have evolved through the use of patterning mechanisms already acting on skeletal elements of the jaws. In general, genetic and morphological approaches identify similar types of modules in the dentition, but the data are not yet sufficient to identify exact correspondences. It is speculated that modularity may be achieved by gene expression differences between teeth or by differences in the time of their development, causing mutations to have cumulative effects on later–developing teeth. The mammalian dentition, for which virtually all of the available developmental genetic data have been collected, represents a small subset of the dental diversity present in vertebrates as a whole. In particular, teleost fishes may have a much more extensive dentition. Extension of research on the genetic control of tooth development to this and other vertebrate groups has great potential to further the understanding of modularity in the dentition.

scholarly journals Bilateral Six Cusped and Three Rooted Mandibular First Molars

2011 ◽  
Vol 2 (3) ◽  
pp. 255-258
Author(s):  
Karthik Venkataraghavan ◽  
P Praveen ◽  
A Anantharaj ◽  
S Prathibha Rani ◽  
Murali B Krishnan
Keyword(s):  
Clinical Examination ◽  
Tooth Development ◽  
Branchial Arch ◽  
Signaling Molecules ◽  
Chief Complaint ◽  
Oral Epithelium ◽  
Wnt Proteins ◽  
Mandibular Molar ◽  
Multiple Signaling ◽  
Surface Occurrence

ABSTRACT Teeth are vertebrate organs that arise from complex and progressive interactions between an ectoderm, the oral epithelium and an underlying mesenchyme. A significant amount of research has focused on determining the processes that initiate tooth development. It is widely accepted that there is a factor (multiple signaling molecules, including BMPs, FGFs, Shh and Wnt proteins) within the tissues of the first branchial arch that is necessary for the development of teeth. A 9-year-old reported to our department with the chief complaint of pain in the lower right back teeth region. On clinical examination, mandibular molars revealed the presence of an extra cusp on the lingual surface. Occurrence of six cusps in permanent mandibular molar is a rare phenomenon, and number of cases reported is very few.

Temporal Control of WNT Activity Regulates Tooth Number in Fish

2018 ◽  
Vol 98 (3) ◽  
pp. 339-346
Author(s):  
J.S. Shim ◽  
B. Kim ◽  
H.C. Park ◽  
J.J. Ryu
Keyword(s):  
Cell Polarity ◽  
Normal Development ◽  
Tooth Development ◽  
Dependent Manner ◽  
Transgenic Models ◽  
Loss Of Function ◽  
Tooth Number ◽  
Pharmacologic Inhibition

Wnts determine cell polarity, cell proliferation, and cell differentiation during embryogenesis and play an essential role during tooth development initiation and morphogenesis. Wnt/β-catenin signaling has a time-dependent role in development because various signaling molecules that mutually interact are involved in the pathway, and tight regulation of the pathway is essential for normal development. Studies investigating how the Wnt/β-catenin signaling pathway controls the different stages of tooth development are rare. Specifically, the effects of Wnt/β-catenin signaling loss of function on different stages of tooth development are currently unknown. Here, we report the stage-dependent role of Wnt/β-catenin signaling in tooth development. In vivo loss and gain of function of Wnt/β-catenin signaling were implemented through the genetic overexpression of DKK1 with heat shock–inducible transgenic models and the pharmacologic inhibition of β-catenin destruction complex formation in zebrafish, respectively. We demonstrated that transient inhibition of Wnt/β-catenin signaling interrupted tooth development in a stage-dependent manner and conditional activation of Wnt/β-catenin signaling during 4V morphogenesis inhibited the development of 3V. These findings suggest that Wnt/β-catenin signaling plays an important role in the morphogenesis of teeth and the initiation of sequential tooth development in a stage-dependent manner.

scholarly journals A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Joanne M. Hildebrand ◽  
Bernice Lo ◽  
Sara Tomei ◽  
Valentina Mattei ◽  
Samuel N. Young ◽  
...  
Keyword(s):  
Potential Role ◽  
Autosomal Dominant ◽  
Inflammatory Diseases ◽  
Diabetic Patients ◽  
Incomplete Penetrance ◽  
Loss Of Function ◽  
Healthy Sibling ◽  
Dominant Disease ◽  
Terminal Effector

AbstractMaturity-onset diabetes of the young, MODY, is an autosomal dominant disease with incomplete penetrance. In a family with multiple generations of diabetes and several early onset diabetic siblings, we found the previously reported P33T PDX1 damaging mutation. Interestingly, this substitution was also present in a healthy sibling. In contrast, a second very rare heterozygous damaging mutation in the necroptosis terminal effector, MLKL, was found exclusively in the diabetic family members. Aberrant cell death by necroptosis is a cause of inflammatory diseases and has been widely implicated in human pathologies, but has not yet been attributed functions in diabetes. Here, we report that the MLKL substitution observed in diabetic patients, G316D, results in diminished phosphorylation by its upstream activator, the RIPK3 kinase, and no capacity to reconstitute necroptosis in two distinct MLKL−/− human cell lines. This MLKL mutation may act as a modifier to the P33T PDX1 mutation, and points to a potential role of impairment of necroptosis in diabetes. Our findings highlight the importance of family studies in unraveling MODY’s incomplete penetrance, and provide further support for the involvement of dysregulated necroptosis in human disease.

scholarly journals Non-productive angiogenesis disassembles Aß plaque-associated blood vessels

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Maria I. Alvarez-Vergara ◽  
Alicia E. Rosales-Nieves ◽  
Rosana March-Diaz ◽  
Guiomar Rodriguez-Perinan ◽  
Nieves Lara-Ureña ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Vessels ◽  
Molecular Signature ◽  
Loss Of Function ◽  
Local Loss ◽  
Microglial Phagocytosis ◽  
Vascular Phenotype ◽  
Cerebral Microvasculature ◽  
Vascular Component

AbstractThe human Alzheimer’s disease (AD) brain accumulates angiogenic markers but paradoxically, the cerebral microvasculature is reduced around Aß plaques. Here we demonstrate that angiogenesis is started near Aß plaques in both AD mouse models and human AD samples. However, endothelial cells express the molecular signature of non-productive angiogenesis (NPA) and accumulate, around Aß plaques, a tip cell marker and IB4 reactive vascular anomalies with reduced NOTCH activity. Notably, NPA induction by endothelial loss of presenilin, whose mutations cause familial AD and which activity has been shown to decrease with age, produced a similar vascular phenotype in the absence of Aß pathology. We also show that Aß plaque-associated NPA locally disassembles blood vessels, leaving behind vascular scars, and that microglial phagocytosis contributes to the local loss of endothelial cells. These results define the role of NPA and microglia in local blood vessel disassembly and highlight the vascular component of presenilin loss of function in AD.

scholarly journals CircHIPK3 regulates the autophagy and apoptosis of hypoxia/reoxygenation-stimulated cardiomyocytes via the miR-20b-5p/ATG7 axis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Zhimei Qiu ◽  
Yan Wang ◽  
Weiwei Liu ◽  
Chaofu Li ◽  
Ranzun Zhao ◽  
...  
Keyword(s):  
Cell Injury ◽  
Ischemia Reperfusion ◽  
Circular Rna ◽  
Control Group ◽  
Loss Of Function ◽  
Cardiomyocyte Autophagy ◽  
Myocardial Ischemia Reperfusion ◽  
Injury Research ◽  
Hypoxia Reoxygenation

AbstractAutophagy and apoptosis are involved in myocardial ischemia/reperfusion (I/R) injury. Research indicates that circular RNA HIPK3 (circHIPK3) is crucial to cell autophagy and apoptosis in various cancer types. However, the role of circHIPK3 in the regulation of cardiomyocyte autophagy and apoptosis during I/R remains unknown. Our study aimed to examine the regulatory effect of circHIPK3 during myocardial I/R and investigate its mechanism in cardiomyocyte autophagy and apoptosis. Methods and results. The expression of circHIPK3 was upregulated during myocardial I/R injury and hypoxia/reoxygenation (H/R) injury of cardiomyocytes. To study the potential role of circHIPK3 in myocardial H/R injury, we performed gain-of-function and loss-of-function analyses of circHIPK3 in cardiomyocytes. Overexpression of circHIPK3 significantly promoted H/R-induced cardiomyocyte autophagy and cell injury (increased intracellular reactive oxygen species (ROS) and apoptosis) compared to those in the control group, while silencing of circHIPK3 showed the opposite effect. Further research found that circHIPK3 acted as an endogenous miR-20b-5p sponge to sequester and inhibit miR-20b-5p activity, resulting in increased ATG7 expression. In addition, miR-20b-5p inhibitors reversed the decrease in ATG7 induced by silencing circHIPK3. Conclusions. CircHIPK3 can accelerate cardiomyocyte autophagy and apoptosis during myocardial I/R injury through the miR-20b-5p/ATG7 axis. These data suggest that circHIPK3 may serve as a potential therapeutic target for I/R.

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