Sonic hedgehog regulates growth and morphogenesis of the tooth

Abstract

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.

Epidermal clock integration and gating of brain signals guarantees skin homeostasis

“…To generate RE/RE mice, Bmal1-stopFL mice ( 5 ) were crossed with K14-Cre mice ( 40 ) and Syt10-Cre mice ( 18 ) mice. The resulting triple heterozygous mice (Arntl stopFL/wt ; K14- Cre tg/wt ;Syt10-Cre tg/wt ) were then crossed with heterozygous Bmal-stopFL mice (Arntl stopFL/wt ; K14-Cre wt/wt ;Syt10-Cre wt/wt ) to generate the five genotypes used in this manuscript: i) wild-type (WT), Arntl wt/wt ; K14-Cre tg/wt ;Syt10-Cre tg/wt ; ii) knockout (KO), Arntl stopFL/stopFL ; K14-Cre wt/wt ;Syt10-Cre wt/wt ; iii) epidermis-RE (epi-RE), Arntl stopFL/stopFL ; K14-Cre tg/wt ;Syt10-Cre wt/wt ; iv) brain-RE: Arntl stopFL/stopFL ; K14-Cre wt/wt ;Syt10-Cre tg/wt ; and v) double reconstituted (RE/RE): Arntl stopFL/stopFL ; K14-Cre tg/wt ;Syt10-Cre tg/wt .…”

Epithelial stem cell homeostasis in Meibomian gland development, dysfunction, and dry eye disease

“…Both male and female mice were used for each experiment. Krox24-KO mice ( 35 ), K14-Cre mice ( 39 ), R26-rtTA mice ( 19 ), and tetO-DTA mice ( 28 ) were purchased from The Jackson Laboratory. The Krox20-Cre mouse line is described in Voiculescu et al ( 24 ), and the Krox20 fl/fl mouse line is described in Taillebourg et al ( 40 ).…”

Signaling Modulation by miRNA-221-3p During Tooth Morphogenesis in Mice

“…At the same time, Shh induced proliferation in a differential manner and determines tooth shape and affects ameloblast polarization through odontoblast differentiation and loss of Shh did not change the expression of other signaling molecules like Fgf4, Bmp2, and Wnt10b (Dassule et al, 2000). However, loss of Shh altered the expression patterns in developing dental tissues suggesting that the loss of Shh results in a change of cell fate, from proliferative to a less proliferative enamel knot-like population (Dassule et al, 2000) which reinforce our hypothesis that miRNA modulation of Shh signaling is crucial for crown morphogenesis and evident in inhibitor-treated specimen. Consistent with our results, inhibition of Shh by 5E1 and Forskolin during tooth organ culture resulted decreased proliferation, increased apoptosis leading to altered tooth phenotype (Cobourne et al, 2001).…”