Article

Ameloblast apoptosis and IGF-1 receptor expression in the continuously erupting rat incisor model

University of Queensland, Brisbane, Queensland, Australia
APOPTOSIS (Impact Factor: 3.69). 01/2000; 4(6):441-7. DOI: 10.1023/A:1009600409421
Source: PubMed

ABSTRACT

Enamel-producing cells (ameloblasts) pass through several phenotypic and functional stages during enamel formation. In the transition between secretory and maturation stages, about one quarter of the ameloblasts suddenly undergo apoptosis. We have studied this phenomenon using the continuously erupting rat incisor model. A special feature of this model is that all stages of ameloblast differentiation are presented within a single longitudinal section of the developing tooth. This permits investigation of the temporal sequence of gene and growth factor receptor expression during ameloblast differentiation and apoptosis. We describe the light and electron microscopic morphology of ameloblast apoptosis and the pattern of insulin-like growth factor-1 receptor expression by ameloblasts in the continuously erupting rat incisor model. In the developing rat incisor, ameloblast apoptosis is associated with downregulated expression of the insulin-like growth factor-1 receptor. These data are consistent with the hypothesis that ameloblasts are "hard wired" for apoptosis and that insulin-like growth factor-1 receptor expression is required to block the default apoptotic pathway. Possible mechanisms of insulin-like growth factor-1 inhibition of ameloblast apoptosis are presented. The rat incisor model may be useful in studies of physiological apoptosis as it presents apoptosis in a predictable pattern in adult tissues.

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    • "GnRH-1 expression was maintained throughout development in dental-epithelial-derived cells on the labial side of the incisor. On this side, dental epithelial cells develop into ameloblasts that are involved in enamel protein synthesis, secretion and biomineralization , and into papillary layer cells that are involved in transport of minerals such as iron and calcium from blood, and in enamel biomineralization (Garant, 1972; Garant et al., 1984; Zeichner-David et al., 1995; Ohshima et al., 1998; Smith, 1998; Fincham et al., 1999; Joseph et al., 1999; Yanagawa et al., 2004). GnRH-1 expression in cells was weak in immature , proximal regions, including preameloblasts and outer dental epithelial cells. "
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    ABSTRACT: Gonadotropin releasing-hormone-1 (GnRH-1) is expressed in mouse incisors during development. In this report, we identify (1) cell type(s) that express GnRH-1 throughout tooth development, (2) the GnRH-1 receptor, and (3) the role of GnRH-1/GnRH-1 receptor signaling in tooth maturation. Results show that GnRH-1-positive cells in dental epithelium differentiate and populate multiple tooth structures including ameloblast and papillary layers that are involved in enamel formation and mineralization. The GnRH-1 receptor was present, and in vitro a GnRH-1 antagonist attenuated incisor GnRH-1 cell expression. In vivo, in mice lacking GnRH-1 (-/-), the incisors were discolored, longer, and more curved compared to wildtype. Elemental analysis of calcium, phosphorus, and iron revealed changes in -/- incisors consistent with GnRH-1 affecting movement of minerals into the dental matrix. In sum, in tooth development a signal transduction pathway exists for GnRH-1 via the GnRH-1 receptor and disruption of such signaling affects incisor growth and biomineralization.
    Full-text · Article · Nov 2007 · Developmental Dynamics
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    ABSTRACT: The development of many embryonic organs is regulated by reciprocal and sequential epithelial-mesenchymal interactions. These interactions are mediated by conserved signaling pathways that are reiteratively used. Cleidocranial dysplasia (CCD) is a congenital syndrome where both bone and tooth development is affected. The syndrome is characterized by short stature, abnormal clavicles, general bone dysplasia, and supernumerary teeth. CCD is caused by mutations in RUNX2, a transcription factor that is a key regulator of osteoblast differentiation and bone formation. The first aim of this study was to analyse the expression of a family of key signal molecules, Bone morphogenetic protein (Bmp) at different stages of tooth development. Bmps have a variety of functions and they were originally discovered as signals inducing ectopic bone formation. We performed a comparative in situ hybridisation analysis of the mRNA expression of Bmp2-7 from initiation of tooth development to differentiation of dental hard tissues. The expression patterns indicated that the Bmps signal between the epithelial and mesenchymal tissues during initiation and morphogenesis of tooth development, as well as during the differentiation of odontoblasts and ameloblasts. Furthermore, they are also part of the signalling networks whereby the enamel knot regulates the patterning of tooth cusps. The second aim was to study the role of Runx2 during tooth development and thereby to gain better understanding of the pathogenesis of the tooth phenotype in CCD. We analysed the tooth phenotype of Runx2 knockout mice and examined the patterns and regulation of Runx2 gene expression.. The teeth of wild-type and Runx2 mutant mice were compared by several methods including in situ hybridisation, tissue culture, bead implantation experiments, and epithelial-mesenchymal recombination studies. Phenotypic analysis of Runx2 -/- mutant tooth development showed that teeth failed to advance beyond the bud stage. Runx2 expression was restricted to dental mesenchyme between the bud and early bell stages of tooth development and it was regulated by epithelial signals, in particular Fgfs. We searched for downstream targets of Runx2 by comparative in situ hybridisation analysis. The expression of Fgf3 was downregulated in the mesenchyme of Runx2 -/- teeth. Shh expression was absent from the enamel knot in the lower molars of Runx2 -/- and reduced in the upper molars. In conclusion, these studies showed that Runx2 regulates key epithelial-mesenchymal interactions that control advancing tooth morphogenesis and histodifferentiation of the epithelial enamel organ. In addition, in the upper molars of Runx2 mutants extra buddings occured at the palatal side of the tooth bud. We suggest that Runx2 acts as an inhibitor of successional tooth formation by preventing advancing development of the buds. Accordingly, we propose that RUNX2 haploinsuffiency in humans causes incomplete inhibition of successional tooth formation and as a result supernumerary teeth. Sikiön ulkopintaa verhoavasta ektodermistä ja sen alaisesta mesenkyymistä kehittyy useita elimiä, joiden kehityksellä on paljon yhteisiä piirteitä. Ektodermaalisten elinten, kuten hampaiden ja rauhasten, solutyypit ja kehityksen anatomia on varsin samankaltaista kaikilla nisäkkäillä. Näiden elinten kehitystä säätelevät epiteelin ja mesenkyymin vuorovaikutukset, joihin osallistuvat yleisten viestiperheiden molekyylit. Pään ja kasvojen luut muodostuvat hermostopienasta peräisin olevasta ektomesenkyymistä. Niiden kehitys tapahtuu ns. välittömän luutumisen mekanismilla eli intramembranoottisesti, kun muut luut muodostuvat rustoisen välivaiheen kautta eli endokondraalisesti. Hampaille ja luille on yhteistä mineralisoituneen kovakudoksen muodostus. Viestimolekyylejä koodaavien geenien mutaatiot aiheuttavat lukuisia kehityshäiriöitä hampaissa ja pään alueen luissa. Kleidokraniaalinen dysplasia on oireyhtymä, jossa on muutoksia sekä luissa että hampaissa. Oireyhtymään liittyy häiriintynyt pituuskasvu, yleinen luiden poikkeavuus, solisluiden epämuodostumat ja ylilukuiset hampaat. Kleidokraniaalisen dysplasian aiheuttaa mutaatio RUNX2 geenissä, joka on välttämätön luusolujen erilaistumiselle. Väitöskirjatyön ensimmäinen tavoite oli tutkia luun morfogeenisten kasvutekijöiden (Bmp) funktiota hampaan kehityksessä. Bmp:t löydettiin alunperin niiden luuta indusoivan kyvyn perusteella, mutta niillä on lisäksi lukuisia funktioita eri elinten kehityksessä. Bmp2, -3, -4, -5, -6, ja -7 geenien ilmentyminen paikannettiin kehittyvissä hiiren hampaissa. Tulokset viittaavat siihen, että Bmp:t välittävät epiteelin ja mesenkyymin välisiä vuorovaikutuksia sekä hampaan kehityksen alkuvaiheissa että hampaan kovakudoksia muodostavien solujen erilaistumisen aikana. Lisäksi Bmp:t ovat osana hampaan signaalikeskuksen, kiillekyhmyn, signaaliverkostossa, joka säätelee hampaan kaavoittumisen. Toinen tavoite oli tutkia Runx2 geenin funktiota hampaan kehityksessä ja siten myös paremmin ymmärtää kleidokraniaalisen dysplasian patogeneesi ja molekyläärinen tausta. Ensin tutkittiin Runx2 geenin ilmentymistä hampaan kehityksen aikana ja todettiin, että ilmentyminen rajautuu hampaan mesenkyymiin silmuvaiheesta varhaiseen kellovaiheeseen. Lisäksi tutkittiin Runx2 poistogeenisten hiirten hampaiden kehitystä ja todettiin, että kehitys pysähtyy silmuvaiheseen. Runx2:n säätelemiä geenejä etsittiin vertailemalla viestiverkostojen geenien ilmenemistä Runx2 poistogeenisella ja normaalilla hiirellä hampaiden kehityksen aikana . Runx2 poistogeenisen hiiren hampaissa todettiin fibroblastikasvutekijäperheeseen kuuluvan Fgf3:n ilmentymisen olevan hyvin alhainen ja lisäksi Shh geenin ilmentymisen puuttuvan alamolaareissa ja vähentyneen ylämolaareista. Tulokset osoittivat, että Runx2 säätelee epiteelin ja mesenkyymin välisiä vuorovaikutuksia, jotka ohjaavat hampaan varhaista kehitystä. Lisäksi havaitsimme ylimääräisiä silmuja Runx2 poistogeenisen hiiren ylämolaareissa ja esitimme että Runx2 estää ylilukuisten hampaiden muodostumista. Tähän viittaa myös se, että yhden Runx2 alleelin puuttuminen kleidokraanialista dysplasiaa sairastavilla potilailla aiheuttaa ylilukuisia hampaita.
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    ABSTRACT: To elucidate the mechanism of root formation in tooth development, we examined the role of insulin-like growth factor I (IGF-I) on early root formation in mandibular first molar teeth from 5-day-old mice. Immunohistochemistry revealed the specific localization of the IGF-I receptor in Hertwig's epithelial root sheath (HERS) in the tooth root. The effect of IGF-I on root development, especially on HERS, was subsequently examined in vitro. The control culture showed normal development of HERS and the periodontium, resembling that in vivo. However, the presence of 100 ng/ml IGF-I resulted in elongation of HERS and increased cell proliferation in its outer layer. These effects were negated by the addition of antibodies specific for IGF-I. Thus, we propose that IGF-I is involved in early root formation by regulating the mitotic activity in the outer layer of HERS.
    No preview · Article · May 2005 · Cell and Tissue Research
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