Dataset Information

Regulation of tooth number by fine-tuning levels of receptor-tyrosine kinase signaling.

ABSTRACT: Much of our knowledge about mammalian evolution comes from examination of dental fossils, because the highly calcified enamel that covers teeth causes them to be among the best-preserved organs. As mammals entered new ecological niches, many changes in tooth number occurred, presumably as adaptations to new diets. For example, in contrast to humans, who have two incisors in each dental quadrant, rodents only have one incisor per quadrant. The rodent incisor, because of its unusual morphogenesis and remarkable stem cell-based continuous growth, presents a quandary for evolutionary biologists, as its origin in the fossil record is difficult to trace, and the genetic regulation of incisor number remains a largely open question. Here, we studied a series of mice carrying mutations in sprouty genes, the protein products of which are antagonists of receptor-tyrosine kinase signaling. In sprouty loss-of-function mutants, splitting of gene expression domains and reduced apoptosis was associated with subdivision of the incisor primordium and a multiplication of its stem cell-containing regions. Interestingly, changes in sprouty gene dosage led to a graded change in incisor number, with progressive decreases in sprouty dosage leading to increasing numbers of teeth. Moreover, the independent development of two incisors in mutants with large decreases in sprouty dosage mimicked the likely condition of rodent ancestors. Together, our findings indicate that altering genetic dosage of an antagonist can recapitulate ancestral dental characters, and that tooth number can be progressively regulated by changing levels of activity of a single signal transduction pathway.

SUBMITTER: Charles C

PROVIDER: S-EPMC3160100 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Regulation of tooth number by fine-tuning levels of receptor-tyrosine kinase signaling.

Charles Cyril C Hovorakova Maria M Ahn Youngwook Y Lyons David B DB Marangoni Pauline P Churava Svatava S Biehs Brian B Jheon Andrew A Lesot Hervé H Balooch Guive G Krumlauf Robb R Viriot Laurent L Peterkova Renata R Klein Ophir D OD

Development (Cambridge, England) 20110901 18

Much of our knowledge about mammalian evolution comes from examination of dental fossils, because the highly calcified enamel that covers teeth causes them to be among the best-preserved organs. As mammals entered new ecological niches, many changes in tooth number occurred, presumably as adaptations to new diets. For example, in contrast to humans, who have two incisors in each dental quadrant, rodents only have one incisor per quadrant. The rodent incisor, because of its unusual morphogenesis ...[more]

PMID: 21862563

Similar Datasets

Project description:Changes in protein levels in different components of the apical junctional complex occur in colorectal cancer (CRC). Claudin?3 is one of the main constituents of tight junctions, and its overexpression can increase the paracellular flux of macromolecules, as well as the malignant potential of CRC cells. The aim of this study was to investigate the molecular mechanisms involved in the regulation of claudin?3 and its prognostic value in CRC. In silico evaluation in each of the CRC consensus molecular subtypes (CMSs) revealed that high expression levels of CLDN3 (gene encoding claudin?3) in CMS2 and CMS3 worsened the patients' long?term survival, whereas a decrease in claudin?3 levels concomitant with a reduction in phosphorylation levels of epidermal growth factor receptor (EGFR) and insulin?like growth factor 1 receptor (IGF1R) could be achieved by inhibiting N?glycan biosynthesis in CRC cells. We also observed that specific inactivation of these receptor tyrosine kinases (RTKs) led to a decrease in claudin?3 levels, and this regulation seems to be mediated by phospholipase C (PLC) and signal transducer and activator of transcription 3 (STAT3) in CRC cells. RTKs are modulated by their N?linked glycans, and inhibition of N?glycan biosynthesis decreased the claudin?3 levels; therefore, we evaluated the correlation between N?glycogenes and CLDN3 expression levels in each of the CRC molecular subtypes. The CMS1 (MSI immune) subtype concomitantly exhibited low expression levels of CLDN3 and N?glycogenes (MGAT5, ST6GAL1, and B3GNT8), whereas CMS2 (canonical) exhibited high gene expression levels of CLDN3 and N?glycogenes (ST6GAL1 and B3GNT8). A robust positive correlation was also observed between CLDN3 and B3GNT8 expression levels in all CMSs. These results support the hypothesis of a mechanism integrating RTK signaling and N?glycosylation for the regulation of claudin?3 levels in CRC, and they suggest that CLDN3 expression can be used to predict the prognosis of patients identified as CMS2 or CMS3.

Project description:Fms-like tyrosine kinase 3 (FLT3) plays an important role in hematopoietic differentiation, and constitutively active FLT3 mutant proteins contribute to the development of acute myeloid leukemia. Little is known about the protein-tyrosine phosphatases (PTP) affecting the signaling activity of FLT3. To identify such PTP, myeloid cells expressing wild type FLT3 were infected with a panel of lentiviral pseudotypes carrying shRNA expression cassettes targeting different PTP. Out of 20 PTP tested, expressed in hematopoietic cells, or presumed to be involved in oncogenesis or tumor suppression, DEP-1 (PTPRJ) was identified as a PTP negatively regulating FLT3 phosphorylation and signaling. Stable 32D myeloid cell lines with strongly reduced DEP-1 levels showed site-selective hyperphosphorylation of FLT3. In particular, the sites pTyr-589, pTyr-591, and pTyr-842 involved in the FLT3 ligand (FL)-mediated activation of FLT3 were hyperphosphorylated the most. Similarly, acute depletion of DEP-1 in the human AML cell line THP-1 caused elevated FLT3 phosphorylation. Direct interaction of DEP-1 and FLT3 was demonstrated by "substrate trapping" experiments showing association of DEP-1 D1205A or C1239S mutant proteins with FLT3 by co-immunoprecipitation. Moreover, activated FLT3 could be dephosphorylated by recombinant DEP-1 in vitro. Enhanced FLT3 phosphorylation in DEP-1-depleted cells was accompanied by enhanced FLT3-dependent activation of ERK and cell proliferation. Stable overexpression of DEP-1 in 32D cells and transient overexpression with FLT3 in HEK293 cells resulted in reduction of FL-mediated FLT3 signaling activity. Furthermore, FL-stimulated colony formation of 32D cells expressing FLT3 in methylcellulose was induced in response to shRNA-mediated DEP-1 knockdown. This transforming effect of DEP-1 knockdown was consistent with a moderately increased activation of STAT5 upon FL stimulation but did not translate into myeloproliferative disease formation in the 32D-C3H/HeJ mouse model. The data indicate that DEP-1 is negatively regulating FLT3 signaling activity and that its loss may contribute to but is not sufficient for leukemogenic cell transformation.

Dataset Information

Regulation of tooth number by fine-tuning levels of receptor-tyrosine kinase signaling.

Publications

Regulation of tooth number by fine-tuning levels of receptor-tyrosine kinase signaling.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets