Biomedical subjects

Marianna Bei

Publications and source records attributed to Marianna Bei.

4 recordsLinked to original sources

PubMed2006

Modification of Msx1 by SUMO-1.

The small ubiquitin-related modifier SUMO reversibly modifies many proteins, including promoter-specific transcription factors. Genetic studies in both humans and mice indicate that the Msx1 transcription factor is associated with specific disorders, including cleft palate. We show that Msx1 conjugation to SUMO-1 in vivo is enhanced by an E3 SUMO ligase, PIAS1, suggesting that sumoylation of Msx1 is a new mechanism for modulating the molecular function of Msx1 during organogenesis.

Animals↗

PubMed2004

Runx2 mediates FGF signaling from epithelium to mesenchyme during tooth morphogenesis.

Runx2 (Cbfa1) is a runt domain transcription factor that is essential for bone development and tooth morphogenesis. Teeth form as ectodermal appendages and their development is regulated by interactions between the epithelium and mesenchyme. We have shown previously that Runx2 is expressed in the dental mesenchyme and regulated by FGF signals from the epithelium, and that tooth development arrests at late bud stage in Runx2 knockout mice [Development 126 (1999) 2911]. In the present study, we have continued to clarify the role of Runx2 in tooth development and searched for downstream targets of Runx2 by extensive in situ hybridization analysis. The expression of Fgf3 was downregulated in the mesenchyme of Runx2 mutant teeth. FGF-soaked beads failed to induce Fgf3 expression in Runx2 mutant dental mesenchyme whereas in wild-type mesenchyme they induced Fgf3 in all explants indicating a requirement of Runx2 for transduction of FGF signals. Fgf3 was absent also in cultured Runx2-/- calvarial cells and it was induced by overexpression of Runx2. Furthermore, Runx2 was downregulated in Msx1 mutant tooth germs, indicating that it functions in the dental mesenchyme between Msx1 and Fgf3. Shh expression was absent from the epithelial enamel knot in lower molars of Runx2 mutant and reduced in upper molars. However, other enamel knot marker genes were expressed normally in mutant upper molars, while reduced or missing in lower molars. These differences between mutant upper and lower molars may be explained by the substitution of Runx2 function by Runx3, another member of the runt gene family that was upregulated in upper but not lower molars of Runx2 mutants. Shh expression in mutant enamel knots was not rescued by FGFs in vitro, indicating that in addition to Fgf3, Runx2 regulates other mesenchymal genes required for early tooth morphogenesis. Also, exogenous FGF and SHH did not rescue the morphogenesis of Runx2 mutant molars. We conclude that Runx2 mediates the functions of epithelial FGF signals regulating Fgf3 expression in the dental mesenchyme and that Fgf3 may be a direct target gene of Runx2.

Animals↗

PubMed2004

Msx2 controls ameloblast terminal differentiation.

Late tooth morphogenesis is characterized by a series of events that determine cusp morphogenesis and the histodifferentiation of epithelial cells into enamel-secreting ameloblasts. Mice lacking the homeobox gene Msx2 exhibit defects in cusp morphogenesis and in the process of amelogenesis. To better understand the basis of the Msx2 mutant tooth defects, we have investigated the function of Msx2 during late stages of tooth morphogenesis. Cusp formation is thought to be under the control of the enamel knot, which has been proposed to act as an organizing center during this process (Vaahtokari et al. [ 1996] Mech. Dev. 54:39-43). Bone morphogenetic protein-4 (BMP4) has been suggested to mediate termination of enamel knot signaling by means of regulation of programmed cell death (Jernvall et al. [ 1998] Development 125:161-169). Here, we show that Bmp4 expression in the enamel knot is Msx2-dependent. We further show that during amelogenesis Msx2 is required for the expression of the extracellular matrix gene Laminin 5 alpha 3, which is known to play an essential role during ameloblast differentiation. This result thus provides a paradigm for understanding how transcription factors and extracellular matrix can be integrated into a developmental pathway controlling cell differentiation.

Amelogenesis↗

PubMed2002

Shh signaling within the dental epithelium is necessary for cell proliferation, growth and polarization.

Sonic hedgehog (Shh), a member of the mammalian Hedgehog (Hh) family, plays a key role during embryogenesis and organogenesis. Tooth development, odontogenesis, is governed by sequential and reciprocal epithelial-mesenchymal interactions. Genetic removal of Shh activity from the dental epithelium, the sole source of Shh during tooth development, alters tooth growth and cytological organization within both the dental epithelium and mesenchyme of the tooth. In this model it is not clear which aspects of the phenotype are the result of the direct action of Shh on a target tissue and which are indirect effects due to deficiencies in reciprocal signalings between the epithelial and mesenchymal components. To distinguish between these two alternatives and extend our understanding of Shh's actions in odontogenesis, we have used the Cre-loxP system to remove Smoothened (Smo) activity in the dental epithelium. Smo, a seven-pass membrane protein is essential for the transduction of all Hh signals. Hence, removal of Smo activity from the dental epithelium should block Shh signaling within dental epithelial derivatives while preserving normal mesenchymal signaling. Here we show that Shh-dependent interactions occur within the dental epithelium itself. The dental mesenchyme develops normally up until birth. In contrast, dental epithelial derivatives show altered proliferation, growth, differentiation and polarization. Our approach uncovers roles for Shh in controlling epithelial cell size, organelle development and polarization. Furthermore, we provide evidence that Shh signaling between ameloblasts and the overlying stratum intermedium may involve subcellular localization of Patched 2 and Gli1 mRNAs, both of which are targets of Shh signaling in these cells.

Ameloblasts↗