Dataset Information

Primary cilia regulate Shh activity in the control of molar tooth number.

ABSTRACT: Primary cilia mediate Hh signalling and mutations in their protein components affect Hh activity. We show that in mice mutant for a cilia intraflagellar transport (IFT) protein, IFT88/polaris, Shh activity is increased in the toothless diastema mesenchyme of the embryonic jaw primordia. This results in the formation of ectopic teeth in the diastema, mesial to the first molars. This phenotype is specific to loss of polaris activity in the mesenchyme since loss of Polaris in the epithelium has no detrimental affect on tooth development. To further confirm that upregulation of Shh activity is responsible for the ectopic tooth formation, we analysed mice mutant for Gas1, a Shh protein antagonist in diastema mesenchyme. Gas1 mutants also had ectopic diastema teeth and accompanying increased Shh activity. In this context, therefore, primary cilia exert a specific negative regulatory effect on Shh activity that functions to repress tooth formation and thus determine tooth number. Strikingly, the ectopic teeth adopt a size and shape characteristic of premolars, a tooth type that was lost in mice around 50-100 million years ago.

SUBMITTER: Ohazama A

PROVIDER: S-EPMC2727556 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Primary cilia regulate Shh activity in the control of molar tooth number.

Ohazama Atsushi A Haycraft Courtney J CJ Seppala Maisa M Blackburn James J Ghafoor Sarah S Cobourne Martyn M Martinelli David C DC Fan Chen-Ming CM Peterkova Renata R Lesot Herve H Yoder Bradley K BK Sharpe Paul T PT

Development (Cambridge, England) 20090211 6

Primary cilia mediate Hh signalling and mutations in their protein components affect Hh activity. We show that in mice mutant for a cilia intraflagellar transport (IFT) protein, IFT88/polaris, Shh activity is increased in the toothless diastema mesenchyme of the embryonic jaw primordia. This results in the formation of ectopic teeth in the diastema, mesial to the first molars. This phenotype is specific to loss of polaris activity in the mesenchyme since loss of Polaris in the epithelium has no ...[more]

PMID: 19211681

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Project description:Investigating the molecular basis for tooth shape variation provides an important glimpse into the evolution of tooth function. We recently showed that loss of mesenchymal BMP7 is sufficient to alter morphology and function of the toothrow. Here we report on the underlying mechanism. Expression of mesenchymal Bmp7 is observed at sites where mineralization is initiated, in tooth cusps of developing molars. Neural crest-specific deletion of Bmp7 (Bmp7ncko) resulted in a complete lack of dentin/enamel formation at birth, the time when mineralization is normally initiated in the upper molars, similar to what was observed in Bmp2ncko mice. Unlike loss of Bmp2, loss of Bmp7 did not affect odontoblast polarization and did not significantly alter the levels of pSmad1/5/8, but almost completely abolished canonical Wnt signaling in (pre)-ameloblasts. Tooth mineralization resumed with a 48-h delay allowing for additional mesenchymal proliferation. Enamel volume was still reduced at P4 and P8, but was comparable in erupted teeth, which were broader and had altered cusp shapes. Tooth eruption was also delayed. Overall, enamel appeared inconspicuous, although some structural changes along with reduced mineral density could be observed. Loss of Bmp7 led to an increase in mesenchymal Bmp6 suggesting an interplay between Bmp6 and Bmp7 in the regulation of mineralization initiation. Our findings show that regulation of the onset of tooth mineralization is a hitherto unsuspected mechanism controlling tooth shape variation. Initiation of tooth mineralization is regulated by a complex epithelial-mesenchymal Bmp/Wnt-signaling network to which Bmp7 contributes. This network is separate and independent of the Bmp2-signaling network regulating odontoblast cell polarization. From an evolutionary perspective, addition of Bmp7 as initiator of tooth mineralization might be akin to an upgrade of an existing computer operating system. While not essential, it provides obviously sufficient advantage warranting its evolutionary incorporation.

Dataset Information

Primary cilia regulate Shh activity in the control of molar tooth number.

Publications

Primary cilia regulate Shh activity in the control of molar tooth number.

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