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T Mustonen

Publications and source records attributed to T Mustonen.

12 recordsLinked to original sources
PubMed2001

TNF signaling via the ligand-receptor pair ectodysplasin and edar controls the function of epithelial signaling centers and is regulated by Wnt and activin during tooth organogenesis.

Ectodermal dysplasia syndromes affect the development of several organs, including hair, teeth, and glands. The recent cloning of two genes responsible for these syndromes has led to the identification of a novel TNF family ligand, ectodysplasin, and TNF receptor, edar. This has indicated a developmental regulatory role for TNFs for the first time. Our in situ hybridization analysis of the expression of ectodysplasin (encoded by the Tabby gene) and edar (encoded by the downless gene) during mouse tooth morphogenesis showed that they are expressed in complementary patterns exclusively in ectodermal tissue layer. Edar was expressed reiteratively in signaling centers regulating key steps in morphogenesis. The analysis of the effects of eight signaling molecules in the TGFbeta, FGF, Hh, Wnt, and EGF families in tooth explant cultures revealed that the expression of edar was induced by activinbetaA, whereas Wnt6 induced ectodysplasin expression. Moreover, ectodysplasin expression was downregulated in branchial arch epithelium and in tooth germs of Lef1 mutant mice, suggesting that signaling by ectodysplasin is regulated by LEF-1-mediated Wnt signals. The analysis of the signaling centers in tooth germs of Tabby mice (ectodysplasin null mutants) indicated that in the absence of ectodysplasin the signaling centers were small. However, no downstream targets of ectodysplasin signaling were identified among several genes expressed in the signaling centers. We conclude that ectodysplasin functions as a planar signal between ectodermal compartments and regulates the function, but not the induction, of epithelial signaling centers. This TNF signaling is tightly associated with epithelial-mesenchymal interactions and with other signaling pathways regulating organogenesis. We suggest that activin signaling from mesenchyme induces the expression of the TNF receptor edar in the epithelial signaling centers, thus making them responsive to Wnt-induced ectodysplasin from the nearby ectoderm. This is the first demonstration of integration of the Wnt, activin, and TNF signaling pathways.

Activins↗
PubMed1999

Cusp patterning defect in Tabby mouse teeth and its partial rescue by FGF.

Tabby is a mouse mutant characterized by deficient development of the ectodermal organs: teeth, hair, and a subset of glands. Ectodysplasin, the protein encoded by the Tabby gene, was recently identified as a novel TNF-like transmembrane protein but little is known about its function. We have examined the Tabby tooth phenotype in detail by analysis of the adult and embryonic teeth. Tabby first molars had an obvious defect in cusp patterning as the number of cusps was reduced and the buccal and lingual cusps were joined. The disturbance in development was first visible morphologically in the bud stage molar. The primary enamel knot in a cap stage Tabby tooth expressed all enamel knot markers analyzed but was smaller than wild type and the first pair of developing secondary enamel knots was fused. We propose that the Tabby tooth phenotype is due to growth retardation during early stages of development which leads to reduced signaling from the primary enamel knot, followed by deficient growth of the dental epithelium and lack of formation of the last developing secondary enamel knots. The ectodysplasin transcripts were expressed in the outer enamel epithelium and dental lamina. When cultured in vitro Tabby bud/cap stage molars formed fewer cusps than wild-type controls. This phenotype was not rescued by exogenously added EGF despite the previously proposed link between Tabby and EGF. Instead FGF-10 partially restored morphogenesis and stimulated the development of additional tooth cusps in cultured Tabby molars.

Animals↗
PubMed1999

Localization of putative stem cells in dental epithelium and their association with Notch and FGF signaling.

The continuously growing mouse incisor is an excellent model to analyze the mechanisms for stem cell lineage. We designed an organ culture method for the apical end of the incisor and analyzed the epithelial cell lineage by 5-bromo-2'-deoxyuridine and DiI labeling. Our results indicate that stem cells reside in the cervical loop epithelium consisting of a central core of stellate reticulum cells surrounded by a layer of basal epithelial cells, and that they give rise to transit-amplifying progeny differentiating into enamel forming ameloblasts. We identified slowly dividing cells among the Notch1-expressing stellate reticulum cells in specific locations near the basal epithelial cells expressing lunatic fringe, a secretory molecule modulating Notch signaling. It is known from tissue recombination studies that in the mouse incisor the mesenchyme regulates the continuous growth of epithelium. Expression of Fgf-3 and Fgf-10 were restricted to the mesenchyme underlying the basal epithelial cells and the transit-amplifying cells expressing their receptors Fgfr1b and Fgfr2b. When FGF-10 protein was applied with beads on the cultured cervical loop epithelium it stimulated cell proliferation as well as expression of lunatic fringe. We present a model in which FGF signaling from the mesenchyme regulates the Notch pathway in dental epithelial stem cells via stimulation of lunatic fringe expression and, thereby, has a central role in coupling the mitogenesis and fate decision of stem cells.

Ameloblasts↗
PubMed1998

Cardiovascular failure in mouse embryos deficient in VEGF receptor-3.

Vascular endothelial growth factor (VEGF) is a key regulator of blood vessel development in embryos and angiogenesis in adult tissues. Unlike VEGF, the related VEGF-C stimulates the growth of lymphatic vessels through its specific lymphatic endothelial receptor VEGFR-3. Here it is shown that targeted inactivation of the gene encoding VEGFR-3 resulted in defective blood vessel development in early mouse embryos. Vasculogenesis and angiogenesis occurred, but large vessels became abnormally organized with defective lumens, leading to fluid accumulation in the pericardial cavity and cardiovascular failure at embryonic day 9.5. Thus, VEGFR-3 has an essential role in the development of the embryonic cardiovascular system before the emergence of the lymphatic vessels.

Animals↗
PubMed1995

Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development.

We have recently cloned the human fms-like tyrosine kinase 4 gene FLT4, whose protein product is related to two vascular endothelial growth factor receptors FLT1 and KDR/FLK1. Here the expression of FLT4 has been analyzed by in situ hybridization during mouse embryogenesis and in adult human tissues. The FLT4 mRNA signals first became detectable in the angioblasts of head mesenchyme, the cardinal vein, and extraembryonally in the allantois of 8.5-day postcoitus (p.c.) embryos. In 12.5-day p.c. embryos, the FLT4 signal decorated developing venous and presumptive lymphatic endothelia, but arterial endothelia were negative. During later stages of development, FLT4 mRNA became restricted to vascular plexuses devoid of red cells, representing developing lymphatic vessels. Only the lymphatic endothelia and some high endothelial venules expressed FLT4 mRNA in adult human tissues. Increased expression occurred in lymphatic sinuses in metastatic lymph nodes and in lymphangioma. Our results suggest that FLT4 is a marker for lymphatic vessels and some high endothelial venules in human adult tissues. They also support the theory on the venous origin of lymphatic vessels.

Adenocarcinoma↗
PubMed1995

Participation of children with autism and nondisabled peers in a cooperatively structured community art program.

Two groups (one younger, one older) of children with autism participated in monthly art activities with same-age nondisabled peers at a children's museum. The study sought to investigate the feasibility of offering a cooperatively structured art education class for students with autism and nondisabled students, and to evaluate the effect of joint participation on the students' interactions with one another. Results indicated that both groups of children with autism were targeted for interactions from nondisabled peers significantly more often during intervention than during baseline, even though positive social interaction bids by nondisabled peers were rarely reciprocated and hardly ever initiated by peers with autism.

Art Therapy↗
PubMed1994

Vascular endothelial growth factor is induced in response to transforming growth factor-beta in fibroblastic and epithelial cells.

Transforming growth factor beta (TGF-beta) is a multifunctional polypeptide that regulates the proliferation and differentiation of various cells and has an angiogenic effect in vivo, although it inhibits the growth of cultured endothelial cells. We report here that TGF-beta treatment of quiescent cultures of mouse embryo-derived AKR-2B cells, which are growth-stimulated by TGF-beta, and human lung adenocarcinoma A549 cells, which are growth-inhibited by TGF-beta, results in the induction of vascular endothelial growth factor (VEGF) mRNA and protein. Maximal VEGF mRNA levels occurred 4-8 h after stimulation with a decline to background levels in 24 h. In contrast, the related placenta growth factor mRNA was not induced by TGF-beta in these cells. No VEGF receptor mRNA was seen in AKR-2B cells. Also, TGF-beta treatment of endothelial cells, which express the FLT1 and KDR/FLK-1 receptors for VEGF, did not cause VEGF induction. Because VEGF is known to be a strong angiogenic factor for endothelial cells, the results suggest that the angiogenic effect of TGF-beta on endothelial cells in blood vessels may be mediated at least partly by a paracrine induction of VEGF in other surrounding cell types.

Animals↗
PubMed1994

BMX, a novel nonreceptor tyrosine kinase gene of the BTK/ITK/TEC/TXK family located in chromosome Xp22.2.

The Bmx sequence was identified and cloned during our search for novel tyrosine kinase genes expressed in human bone marrow cells. Bmx cDNA comprises a long open reading frame of 675 amino acids, containing one SH3, one SH2 and one tyrosine kinase domain, which are about 70% identical with Btk, Itk and Tec and somewhat less with Txk tyrosine kinase sequences. The amino terminal sequences of these four tyrosine kinases are about 40% identical and each contains a so-called pleckstrin homology domain. The 2.7 kb Bmx mRNA was expressed in endothelial cells and several human tissues by Northern blotting and an 80 kD Bmx polypeptide was detected in human endothelial cells. Immunoprecipitates of COS cells transfected with a Bmx expression vector and NIH3T3 cells expressing a Bmx retrovirus contained a tyrosyl phosphorylated Bmx polypeptide of similar molecular weight. The BMX gene was located in chromosomal band Xp22.2 between the DXS197 and DXS207 loci. Interestingly, chromosome X also contains the closest relative of BMX, the BTK gene, implicated in X-linked agammaglobulinemia. The BMX gene thus encodes a novel nonreceptor tyrosine kinase, which may play a role in the growth and differentiation of hematopoietic cells.

3T3 Cells↗
PubMed1990

Integrating children with severe disabilities for intensified outdoor education: focus on feasibility.

The feasibility of an intensified (i.e., all-day-for-2-weeks) integrated camping experience for children with and without severe disabilities was evaluated as was the impact of integrated programming on camp staff members' attitudes. Procedures employed for promoting social interactions included positive reinforcement and cooperative learning strategies. Task-analytic procedures were used to teach campers with severe disabilities a domestic skill and a life-long leisure activity. By the end of the 2 weeks, children with severe disabilities demonstrated substantially improved skills in targeted activities. Furthermore, campers without disabilities substantially increased their prosocial interaction bids, and ratings reflective of friendship increased significantly. Also, staff members' perceptions of operating an integrated camp versus a segregated one and their perceptions of the presence of participants with disabilities as facilitative of camp operations improved significantly.

Adolescent↗