Reciprocal interactions between epithelial and mesenchymal tissues play a fundamental role in the morphogenesis of teeth and regulate all aspects of tooth development. Extensive studies on mouse tooth development over the past 25 years have uncovered the molecular details of the signaling networks mediating these interactions (reviewed by Jussila & Thesleff, 2012; Lan, Jia, & Jiang, 2014). Five conserved signaling pathways, namely, the Wnt, BMP, FGF, Shh, and Eda, are involved in the mediation of the successive reciprocal epithelial-mesenchymal cross talk which follows the general principle of morphogenetic interactions (Davidson, 1993). The pathways regulate the expression of transcription factors which confer the identity of dental epithelium and mesenchyme. The signals and transcription factors are integrated in complex signaling networks whose fine-tuning allows the generation of the variation in tooth morphologies. In this review, we describe the principles and molecular mechanisms of the epithelial-mesenchymal interactions regulating successive stages of tooth formation: (i) the initiation of tooth development, with special reference to the shift of tooth-forming potential from epithelium to mesenchyme; (ii) the morphogenesis of the tooth crown, focusing on the roles of epithelial signaling centers; (iii) the differentiation of odontoblasts and ameloblasts, which produce dentin and enamel, respectively; and (iv) the maintenance of dental stem cells, which support the continuous growth of teeth.

Tissue Interactions Regulating Tooth Development and Renewal.

The basement membrane is a thin but dense, sheet-like specialized type of extracellular matrix that has remarkably diverse functions tailored to individual tissues and organs. Tightly controlled spatial and temporal changes in its composition and structure contribute to the diversity of basement membrane functions. These different basement membranes undergo dynamic transformations throughout animal life, most notably during development. Numerous developmental mechanisms are regulated or mediated by basement membranes, often by a combination of molecular and mechanical processes. A particularly important process involves cell transmigration through a basement membrane because of its link to cell invasion in disease. While developmental and disease processes share some similarities, what clearly distinguishes the two is dysregulation of cells and extracellular matrices in disease. With its relevance to many developmental and disease processes, the basement membrane is a vitally important area of research that may provide novel insights into biological mechanisms and development of innovative therapeutic approaches. Here we present a review of developmental and disease dynamics of basement membranes in Caenorhabditis elegans, Drosophila, and vertebrates.

/pdf/basement-membranes-in-development-and-disease-1ba39cl6ni.pdf

Basement Membranes in Development and Disease.

The tooth provides an excellent system for deciphering the molecular mechanisms of organogenesis, and has thus been of longstanding interest to developmental and stem cell biologists studying embryonic morphogenesis and adult tissue renewal. In recent years, analyses of molecular signaling networks, together with new insights into cellular heterogeneity, have greatly improved our knowledge of the dynamic epithelial-mesenchymal interactions that take place during tooth development and homeostasis. Here, we review recent progress in the field of mammalian tooth morphogenesis and also discuss the mechanisms regulating stem cell-based dental tissue homeostasis, regeneration and repair. These exciting findings help to lay a foundation that will ultimately enable the application of fundamental research discoveries toward therapies to improve oral health.

Molecular and cellular mechanisms of tooth development, homeostasis and repair.

Engineered Tissue Folding by Mechanical Compaction of the Mesenchyme

Dental root formation is a dynamic process in which mesenchymal cells migrate toward the site of the future root, differentiate and secrete dentin and cementum. However, the identities of dental mesenchymal progenitors are largely unknown. Here we show that cells expressing osterix are mesenchymal progenitors contributing to all relevant cell types during morphogenesis. The majority of cells expressing parathyroid hormone-related peptide (PTHrP) are in the dental follicle and on the root surface, and deletion of its receptor (PPR) in these progenitors leads to failure of eruption and significantly truncated roots lacking periodontal ligaments. The PPR-deficient progenitors exhibit accelerated cementoblast differentiation with upregulation of nuclear factor I/C (Nfic). Deletion of histone deacetylase-4 (HDAC4) partially recapitulates the PPR deletion root phenotype. These findings indicate that PPR signalling in dental mesenchymal progenitors is essential for tooth root formation, underscoring importance of the PTHrP-PPR system during root morphogenesis and tooth eruption.

Parathyroid hormone receptor signalling in osterix-expressing mesenchymal progenitors is essential for tooth root formation

BMP-SHH Signaling Network Controls Epithelial Stem Cell Fate via Regulation of Its Niche in the Developing Tooth

Coordination between the Hertwig's epithelial root sheath (HERS) and apical papilla (AP) is crucial for proper tooth root development. The hedgehog (Hh) signaling pathway and Nfic are both involved in tooth root development; however, their relationship has yet to be elucidated. Here, we establish a timecourse of mouse molar root development by histological staining of sections, and we demonstrate that Hh signaling is active before and during root development in the AP and HERS using Gli1 reporter mice. The proper pattern of Hh signaling activity in the AP is crucial for the proliferation of dental mesenchymal cells, because either inhibition with Hh inhibitors or constitutive activation of Hh signaling activity in transgenic mice leads to decreased proliferation in the AP and shorter roots. Moreover, Hh activity is elevated in Nfic(-/-) mice, a root defect model, whereas RNA sequencing and in situ hybridization show that the Hh attenuator Hhip is downregulated. ChIP and RNAscope analyses suggest that Nfic binds to the promoter region of Hhip. Treatment of Nfic(-/-) mice with Hh inhibitor partially restores cell proliferation, AP growth and root development. Taken together, our results demonstrate that an Nfic-Hhip-Hh signaling pathway is crucial for apical papilla growth and proper root formation. This discovery provides insight into the molecular mechanisms regulating tooth root development.

/pdf/an-nfic-hedgehog-signaling-cascade-regulates-tooth-root-17j973afge.pdf

An Nfic-hedgehog signaling cascade regulates tooth root development.

Ciliopathies are pleiotropic human diseases resulting from defects of the primary cilium, and these patients often have cleft lip and palate. IFT88 is required for the assembly and function of the primary cilia, which mediate the activity of key developmental signaling pathways. Through whole exome sequencing of a family of three affected siblings with isolated cleft lip and palate, we discovered that they share a novel missense mutation in IFT88 (c.915G>C, p.E305D), suggesting this gene should be considered a candidate for isolated orofacial clefting. In order to evaluate the function of IFT88 in regulating craniofacial development, we generated Wnt1-Cre;Ift88(fl/fl) mice to eliminate Ift88 specifically in cranial neural crest (CNC) cells. Wnt1-Cre;Ift88(fl/fl) pups died at birth due to severe craniofacial defects including bilateral cleft lip and palate and tongue agenesis, following the loss of the primary cilia in the CNC-derived palatal mesenchyme. Loss of Ift88 also resulted in a decrease in neural crest cell proliferation during early stages of palatogenesis as well as a downregulation of the Shh signaling pathway in the palatal mesenchyme. Importantly, Osr2KI-Cre;Ift88(fl/fl) mice, in which Ift88 is lost specifically in the palatal mesenchyme, exhibit isolated cleft palate. Taken together, our results demonstrate that IFT88 has a highly conserved function within the primary cilia of the CNC-derived mesenchyme in the lip and palate region in mice and is a strong candidate as an orofacial clefting gene in humans.

/pdf/intraflagellar-transport-88-ift88-is-crucial-for-f1emytj55r.pdf

Intraflagellar transport 88 (IFT88) is crucial for craniofacial development in mice and is a candidate gene for human cleft lip and palate.

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BMP-SHH Signaling Network Controls Epithelial Stem Cell Fate via Regulation of Its Niche in the Developing Tooth

An Nfic-hedgehog signaling cascade regulates tooth root development.

Intraflagellar transport 88 (IFT88) is crucial for craniofacial development in mice and is a candidate gene for human cleft lip and palate.