An FGF signaling loop sustains the generation of differentiated progeny from stem cells in mouse incisor

Department of Anatomy and Program in Developmental Biology, School of Medicine, University of California at San Francisco, San Francisco, CA 94143-2711, USA.
Development (Impact Factor: 6.46). 02/2008; 135(2):377-85. DOI: 10.1242/dev.015081
Source: PubMed


Rodent incisors grow throughout adult life, but are prevented from becoming excessively long by constant abrasion, which is facilitated by the absence of enamel on one side of the incisor. Here we report that loss-of-function of sprouty genes, which encode antagonists of receptor tyrosine kinase signaling, leads to bilateral enamel deposition, thus impeding incisor abrasion and resulting in unchecked tooth elongation. We demonstrate that sprouty genes function to ensure that enamel-producing ameloblasts are generated on only one side of the tooth by inhibiting the formation of ectopic ameloblasts from self-renewing stem cells, and that they do so by preventing the establishment of an epithelial-mesenchymal FGF signaling loop. Interestingly, although inactivation of Spry4 alone initiates ectopic ameloblast formation in the embryo, the dosage of another sprouty gene must also be reduced to sustain it after birth. These data reveal that the generation of differentiated progeny from a particular stem cell population can be differently regulated in the embryo and adult.

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    • "Thus, hypselodonty allows the continual replenishment of worn tooth structures throughout the lifetime of the animal (Tummers and Thesleff, 2003), whereas even extremely hypsodont teeth are of finite duration. Several genes important for stem-cell-driven dental renewal in extant mammals have been identified (Harada et al., 1999; Klein et al., 2008; Wang et al., 2007), and comparison of voles and mice suggested that prolonged expression of some of these genes could result in taller crowns (Yokohama-Tamaki et al., 2006). In addition, the fossil record has provided extensive information about the evolution of tooth height in large and small mammals (Damuth and Janis, 2011; Janis, 1988; Jardine et al., 2012; Jernvall and Fortelius, 2002). "
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    ABSTRACT: The fossil record is widely informative about evolution, but fossils are not systematically used to study the evolution of stem-cell-driven renewal. Here, we examined evolution of the continuous growth (hypselodonty) of rodent molar teeth, which is fuelled by the presence of dental stem cells. We studied occurrences of 3,500 North American rodent fossils, ranging from 50 million years ago (mya) to 2 mya. We examined changes in molar height to determine whether evolution of hypselodonty shows distinct patterns in the fossil record, and we found that hypselodont taxa emerged through intermediate forms of increasing crown height. Next, we designed a Markov simulation model, which replicated molar height increases throughout the Cenozoic and, moreover, evolution of hypselodonty. Thus, by extension, the retention of the adult stem cell niche appears to be a predictable quantitative rather than a stochastic qualitative process. Our analyses predict that hypselodonty will eventually become the dominant phenotype. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 04/2015; 11(5). DOI:10.1016/j.celrep.2015.03.064 · 8.36 Impact Factor
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    • "The analysis of murine mutants, exhibiting either 2-sided crown analogs or 2-sided root analogs, provides clues regarding the mechanisms of crown-to-root transition. Several murine mutants are known to develop such defects in incisor asymmetry, including Fst and Sprouty nulls (Wang et al., 2004; Klein et al., 2008), as well as Krt14-driven overexpression of Fst and Eda (Mustonen et al., 2003). Although correlative, these studies suggest that molecular cues govern stem cell maintenance, which differentiate brachydont, hypsodont and hypselodont teeth. "
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    ABSTRACT: A major challenge for current evolutionary and developmental biology research is to understand the evolution of morphogenesis and the mechanisms involved. Teeth are well suited for the investigation of developmental processes. In addition, since teeth are composed of hard-mineralized tissues, primarily apatite, that are readily preserved, the evolution of mammals is well documented through their teeth in the fossil record. Hypsodonty, high crowned teeth with shallow roots, and hypselodonty, ever-growing teeth, are convergent innovations that have appeared multiple times since the mammalian radiation 65 million years ago, in all tooth categories (incisors, canines, premolars, and molars). A shift to hypsodonty, or hypselodonty, during mammalian evolution is often, but not necessarily, associated with increasingly abrasive diet during important environmental change events. Although the evolution of hypsodonty and hypselodonty is considered to be the result of heterochrony of development, little has been known about the exact developmental mechanisms at the origin of these morphological traits. Developmental biologists have been intrigued by the mechanism of hypselodonty since it requires the maintenance of continuous crown formation during development via stem cell niche activity. Understanding this mechanism may allow bioengineered tooth formation in humans. Hypsodonty and hypselodonty are thus examples of phenotypic features of teeth that have both impacts in understanding the evolution of mammals and holds promise for human tooth bioengineering.
    Frontiers in Physiology 08/2014; 5:324. DOI:10.3389/fphys.2014.00324 · 3.53 Impact Factor
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    • "In contrast, dental epithelia in molars are not regenerated once molars are developed. DE-SCs share several characteristics with other adult stem cells in regenerative tissues such as slow division, discrete niche, and the ability to differentiate [1], [2]. DE-SCs are supported by a microenvironment within the CL, called the stem cell niche, that plays an important role in maintenance, proliferation, differentiation, and cell fate decisions during dental development [3] as observed in other self-renewing tissues [4]. "
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    ABSTRACT: Cell fates are determined by specific transcriptional programs. Here we provide evidence that the transcriptional coactivator, Mediator 1 (Med1), is essential for the cell fate determination of ectodermal epithelia. Conditional deletion of Med1 in vivo converted dental epithelia into epidermal epithelia, causing defects in enamel organ development while promoting hair formation in the incisors. We identified multiple processes by which hairs are generated in Med1 deficient incisors: 1) dental epithelial stem cells lacking Med 1 fail to commit to the dental lineage, 2) Sox2-expressing stem cells extend into the differentiation zone and remain multi-potent due to reduced Notch1 signaling, and 3) epidermal fate is induced by calcium as demonstrated in dental epithelial cell cultures. These results demonstrate that Med1 is a master regulator in adult stem cells to govern epithelial cell fate.
    PLoS ONE 06/2014; 9(6):e99991. DOI:10.1371/journal.pone.0099991 · 3.23 Impact Factor
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