scholarly journals Gas1 Regulates Patterning of the Murine and Human Dentitions through Sonic Hedgehog

2021 ◽  
pp. 002203452110494
Author(s):  
M. Seppala ◽  
B. Thivichon-Prince ◽  
G.M. Xavier ◽  
N. Shaffie ◽  
I. Sangani ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Tooth Development ◽  
Human Subjects ◽  
Tooth Germ ◽  
Molecular Signaling ◽  
Loss Of Function ◽  
Supernumerary Teeth ◽  
Supernumerary Tooth ◽  
Tooth Number

The mammalian dentition is a serially homogeneous structure that exhibits wide numerical and morphological variation among multiple different species. Patterning of the dentition is achieved through complex reiterative molecular signaling interactions that occur throughout the process of odontogenesis. The secreted signaling molecule Sonic hedgehog (Shh) plays a key role in this process, and the Shh coreceptor growth arrest-specific 1 (Gas1) is expressed in odontogenic mesenchyme and epithelium during multiple stages of tooth development. We show that mice engineered with Gas1 loss-of-function mutation have variation in number, morphology, and size of teeth within their molar dentition. Specifically, supernumerary teeth with variable morphology are present mesial to the first molar with high penetrance, while molar teeth are characterized by the presence of both additional and absent cusps, combined with reduced dimensions and exacerbated by the presence of a supernumerary tooth. We demonstrate that the supernumerary tooth in Gas1 mutant mice arises through proliferation and survival of vestigial tooth germs and that Gas1 function in cranial neural crest cells is essential for the regulation of tooth number, acting to restrict Wnt and downstream FGF signaling in odontogenic epithelium through facilitation of Shh signal transduction. Moreover, regulation of tooth number is independent of the additional Hedgehog coreceptors Cdon and Boc, which are also expressed in multiple regions of the developing tooth germ. Interestingly, further reduction of Hedgehog pathway activity in Shhtm6Amc hypomorphic mice leads to fusion of the molar field and reduced prevalence of supernumerary teeth in a Gas1 mutant background. Finally, we demonstrate defective coronal morphology and reduced coronal dimensions in the molar dentition of human subjects identified with pathogenic mutations in GAS1 and SHH/GAS1, suggesting that regulation of Hedgehog signaling through GAS1 is also essential for normal patterning of the human dentition.

scholarly journals Hedgehog signalling regulates patterning of the murine and human dentitions through Gas1 co-receptor function

2020 ◽  
Author(s):  
Maisa Seppala ◽  
Beatrice Thivichon-Prince ◽  
Guilherme M. Xavier ◽  
Nina Shaffie ◽  
Indiya Sangani ◽  
...  
Keyword(s):  
Tooth Development ◽  
Human Subjects ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Supernumerary Teeth ◽  
Hedgehog Signalling ◽  
Shh Pathway ◽  
Tooth Number ◽  
Cranial Neural Crest Cells ◽  
Tooth Germs

ABSTRACTThe mammalian dentition exhibits wide numerical and morphological variation between different species. The regulation of dental pattern is achieved through complex reiterative molecular signalling interactions that occur through multiple stages of tooth development. We show that mice with loss-of-function in the Hedgehog co-receptor Gas1 have variation in size, morphology and number of teeth within the molar dentition. Specifically, premolar-like supernumerary teeth are present with high penetrance, arising through survival and continued development of vestigial tooth germs. We further demonstrate that Gas1 function in cranial neural crest cells is essential for the regulation of tooth number, acting to restrict Wnt signalling in vestigial tooth germs through facilitation of Shh signalling. Moreover, regulation of tooth number is independent of the additional Hedgehog co-receptors Cdon and Boc. Interestingly, further reduction of Shh pathway activity in a Gas1 mutant background leads to fusion of the molar field and ultimately, developmental arrest of tooth development rather than exacerbating the supernumerary phenotype. Finally, we demonstrate defective coronal morphology in the molar dentition of human subjects carrying GAS1 missense mutations, suggesting that regulation of Hedgehog signalling through GAS1 is also essential for normal patterning of the human dentition.

Tooth development in the ‘crooked’ mouse

Development ◽  
1977 ◽  
Vol 41 (1) ◽  
pp. 279-287
Author(s):  
J. A. Sofaer
Keyword(s):  
Competitive Inhibition ◽  
Tooth Development ◽  
Tooth Germ ◽  
Axial Skeleton ◽  
Tissue Formation ◽  
Supernumerary Teeth ◽  
Hard Tissue ◽  
Dental Lamina ◽  
Dental Abnormalities ◽  
Rates Of Growth

The semidominant gene ‘crooked’ (Cd) in the mouse produces anomalies of the axial skeleton (resulting in a crooked tail), microphthalmia and dental abnormalities, including small molars with simplified cusp patterns that are equivalent to patterns passed through during normal morphodifferentiation. A series of embryonic litters from Cd/ + × Cd / + matings was used to investigate the embryological basis for the dental abnormalities. Microphthalmic embryos were classed as Cd/Cd, and their most normal litter mates were selected as controls (+ / + or Cd / +). An additional set of control embryos came from the inbred strain CBA/Cam (+ / +). Serial sagittal sections of the heads of these embryos were examined microscopically, and the maximum anteroposterior diameters of the developing upper and lower first molars were measured. Reduction in the rates of growth and morphodifferentiation of Cd/Cd first molars, relative to those of litter mate controls, was associated with the appearance of an adjacent abnormal proliferation of the dental lamina. Some proliferations in older embryos showed signs of early tooth germ formation, but many were seen to have regressed and no examples of supernumerary teeth have been found in Cd/Cd adults. Small size of Cd/Cd molars may therefore result from competitive inhibition of molar growth by a transient abnormal laminal proliferation, and Cd/Cd cusp patterns from the relatively premature onset of hard tissue formation during normal but retarded sequences of morphodifferentiation.

scholarly journals Role of Cell Death in Cellular Processes During Odontogenesis

2021 ◽  
Vol 9 ◽  
Author(s):  
John Abramyan ◽  
Poongodi Geetha-Loganathan ◽  
Marie Šulcová ◽  
Marcela Buchtová
Keyword(s):  
Cell Death ◽  
Tooth Development ◽  
Apoptotic Cell ◽  
Tooth Germ ◽  
Oral Epithelium ◽  
Special Focus ◽  
Apoptotic Cells ◽  
Molecular Signaling ◽  
Apoptotic Pathway ◽  
Cellular Processes

The development of a tooth germ in a precise size, shape, and position in the jaw, involves meticulous regulation of cell proliferation and cell death. Apoptosis, as the most common type of programmed cell death during embryonic development, plays a number of key roles during odontogenesis, ranging from the budding of the oral epithelium during tooth initiation, to later tooth germ morphogenesis and removal of enamel knot signaling center. Here, we summarize recent knowledge about the distribution and function of apoptotic cells during odontogenesis in several vertebrate lineages, with a special focus on amniotes (mammals and reptiles). We discuss the regulatory roles that apoptosis plays on various cellular processes during odontogenesis. We also review apoptosis-associated molecular signaling during tooth development, including its relationship with the autophagic pathway. Lastly, we cover apoptotic pathway disruption, and alterations in apoptotic cell distribution in transgenic mouse models. These studies foster a deeper understanding how apoptotic cells affect cellular processes during normal odontogenesis, and how they contribute to dental disorders, which could lead to new avenues of treatment in the future.

scholarly journals A subpopulation of astrocyte progenitors defined by Sonic hedgehog signaling

2022 ◽  
Vol 17 (1) ◽  
Author(s):  
Ellen C. Gingrich ◽  
Kendra Case ◽  
A. Denise R. Garcia
Keyword(s):  
Progenitor Cells ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Adult Brain ◽  
Substantial Contribution ◽  
Molecular Signaling ◽  
Sonic Hedgehog Signaling ◽  
Independent Manner ◽  
Shh Signaling ◽  
Cortical Astrocyte

Abstract Background The molecular signaling pathway, Sonic hedgehog (Shh), is critical for the proper development of the central nervous system. The requirement for Shh signaling in neuronal and oligodendrocyte development in the developing embryo are well established. However, Shh activity is found in discrete subpopulations of astrocytes in the postnatal and adult brain. Whether Shh signaling plays a role in astrocyte development is not well understood. Methods Here, we use a genetic inducible fate mapping approach to mark and follow a population of glial progenitor cells expressing the Shh target gene, Gli1, in the neonatal and postnatal brain. Results In the neonatal brain, Gli1-expressing cells are found in the dorsolateral corner of the subventricular zone (SVZ), a germinal zone harboring astrocyte progenitor cells. Our data show that these cells give rise to half of the cortical astrocyte population, demonstrating their substantial contribution to the cellular composition of the cortex. Further, these data suggest that the cortex harbors astrocytes from different lineages. Gli1 lineage astrocytes are distributed across all cortical layers, positioning them for broad influence over cortical circuits. Finally, we show that Shh activity recurs in mature astrocytes in a lineage-independent manner, suggesting cell-type dependent roles of the pathway in driving astrocyte development and function. Conclusion These data identify a novel role for Shh signaling in cortical astrocyte development and support a growing body of evidence pointing to astrocyte heterogeneity.

scholarly journals Synergistic roles of Wnt modulators R-spondin2 and R-spondin3 in craniofacial morphogenesis and dental development

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nora Alhazmi ◽  
Shannon H. Carroll ◽  
Kenta Kawasaki ◽  
Katherine C. Woronowicz ◽  
Shawn A. Hallett ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Tooth Development ◽  
Bone Development ◽  
Critical Role ◽  
Tooth Germ ◽  
Craniofacial Development ◽  
Craniofacial Skeleton ◽  
Mouse Development ◽  
Tooth Number ◽  
Fin Development

AbstractWnt signaling plays a critical role in craniofacial patterning, as well as tooth and bone development. Rspo2 and Rspo3 are key regulators of Wnt signaling. However, their coordinated function and relative requirement in craniofacial development and odontogensis are poorly understood. We showed that in zebrafish rspo2 and rspo3 are both expressed in osteoprogenitors in the embryonic craniofacial skeleton. This is in contrast to mouse development, where Rspo3 is expressed in osteoprogenitors while Rspo2 expression is not observed. In zebrafish, rspo2 and rspo3 are broadly expressed in the pulp, odontoblasts and epithelial crypts. However, in the developing molars of the mouse, Rspo3 is largely expressed in the dental follicle and alveolar mesenchyme while Rspo2 expression is restricted to the tooth germ. While Rspo3 ablation in the mouse is embryonic lethal, zebrafish rspo3-/- mutants are viable with modest decrease in Meckel’s cartilage rostral length. However, compound disruption of rspo3 and rspo2 revealed synergistic roles of these genes in cartilage morphogenesis, fin development, and pharyngeal tooth development. Adult rspo3−/− zebrafish mutants exhibit a dysmorphic cranial skeleton and decreased average tooth number. This study highlights the differential functions of Rspo2 and Rspo3 in dentocranial morphogenesis in zebrafish and in mouse.

scholarly journals Sonic hedgehog signaling in astrocytes

2020 ◽  
Author(s):  
Steven A. Hill ◽  
Marissa Fu ◽  
A. Denise R. Garcia
Keyword(s):  
Nervous System ◽  
Signaling Pathway ◽  
Functional Properties ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Synapse Formation ◽  
Synaptic Activity ◽  
Molecular Signaling ◽  
Sonic Hedgehog Signaling ◽  
Shh Signaling

Abstract Astrocytes are complex cells that perform a broad array of essential functions in the healthy and injured nervous system. The recognition that these cells are integral components of various processes, including synapse formation, modulation of synaptic activity, and response to injury, underscores the need to identify the molecular signaling programs orchestrating these diverse functional properties. Emerging studies have identified the Sonic hedgehog (Shh) signaling pathway as an essential regulator of the molecular identity and functional properties of astrocytes. Well established as a powerful regulator of diverse neurodevelopmental processes in the embryonic nervous system, its functional significance in astrocytes is only beginning to be revealed. Notably, Shh signaling is active only in discrete subpopulations of astrocytes distributed throughout the brain, a feature that has potential to yield novel insights into functional specialization of astrocytes. Here, we discuss Shh signaling and emerging data that point to essential roles for this pleiotropic signaling pathway in regulating various functional properties of astrocytes in the healthy and injured brain.

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 new function of BMP4: dual role for BMP4 in regulation of Sonic hedgehog expression in the mouse tooth germ

Development ◽  
2000 ◽  
Vol 127 (7) ◽  
pp. 1431-1443 ◽  
Author(s):  
Y. Zhang ◽  
Z. Zhang ◽  
X. Zhao ◽  
X. Yu ◽  
Y. Hu ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Sonic Hedgehog ◽  
Tooth Development ◽  
Tooth Germ ◽  
Signaling Molecules ◽  
Limb Bud ◽  
Wild Type ◽  
Morphogenetic Protein ◽  
In The Wild ◽  
Dental Epithelium

The murine tooth development is governed by sequential and reciprocal epithelial-mesenchymal interactions. Multiple signaling molecules are expressed in the developing tooth germ and interact each other to mediate the inductive tissue interactions. Among them are Sonic hedgehog (SHH), Bone Morphogenetic Protein-2 (BMP2) and Bone Morphogenetic Protein-4 (BMP4). We have investigated the interactions between these signaling molecules during early tooth development. We found that the expression of Shh and Bmp2 is downregulated at E12.5 and E13.5 in the dental epithelium of the Msx1 mutant tooth germ where Bmp4 expression is significantly reduced in the dental mesenchyme. Inhibition of BMP4 activity by noggin resulted in repression of Shh and Bmp2 in wild-type dental epithelium. When implanted into the dental mesenchyme of Msx1 mutants, beads soaked with BMP4 protein were able to restore the expression of both Shh and Bmp2 in the Msx1 mutant epithelium. These results demonstrated that mesenchymal BMP4 represents one component of the signal acting on the epithelium to maintain Shh and Bmp2 expression. In contrast, BMP4-soaked beads repressed Shh and Bmp2 expression in the wild-type dental epithelium. TUNEL assay indicated that this suppression of gene expression by exogenous BMP4 was not the result of an increase in programmed cell death in the tooth germ. Ectopic expression of human Bmp4 to the dental mesenchyme driven by the mouse Msx1 promoter restored Shh expression in the Msx1 mutant dental epithelium but repressed Shh in the wild-type tooth germ in vivo. We further demonstrated that this regulation of Shh expression by BMP4 is conserved in the mouse developing limb bud. In addition, Shh expression was unaffected in the developing limb buds of the transgenic mice in which a constitutively active Bmpr-IB is ectopically expressed in the forelimb posterior mesenchyme and throughout the hindlimb mesenchyme, suggesting that the repression of Shh expression by BMP4 may not be mediated by BMP receptor-IB. These results provide evidence for a new function of BMP4. BMP4 can act upstream to Shh by regulating Shh expression in mouse developing tooth germ and limb bud. Taken together, our data provide insight into a new regulatory mechanism for Shh expression, and suggest that this BMP4-mediated pathway in Shh regulation may have a general implication in vertebrate organogenesis.

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