다중혈관 관상동맥 환자에서 y-문합을 이용하여 양쪽 내흉동맥만을 사용한 우회술의 조기 성적

[신간의 별자리x] 우리/미술, 그리고 ‘슬픔의 박물관’

Without epithelial–mesenchymal transitions, in which polarized epithelial cells are converted into motile cells, multicellular organisms would be incapable of getting past the blastula stage of embryonic development. However, this important developmental programme has a more sinister role in tumour progression. Epithelial–mesenchymal transition provides a new basis for understanding the progression of carcinoma towards dedifferentiated and more malignant states.

Epithelial–mesenchymal transitions in tumour progression

Tight control of cell-cell communication is essential for the generation of a normally patterned embryo. A critical mediator of key cell-cell signaling events during embryogenesis is the highly conserved Wnt family of secreted proteins. Recent biochemical and genetic analyses have greatly enriched our understanding of how Wnts signal, and the list of canonical Wnt signaling components has exploded. The data reveal that multiple extracellular, cytoplasmic, and nuclear regulators intricately modulate Wnt signaling levels. In addition, receptor-ligand specificity and feedback loops help to determine Wnt signaling outputs. Wnts are required for adult tissue maintenance, and perturbations in Wnt signaling promote both human degenerative diseases and cancer. The next few years are likely to see novel therapeutic reagents aimed at controlling Wnt signaling in order to alleviate these conditions.

/pdf/the-wnt-signaling-pathway-in-development-and-disease-z4j8s29ao8.pdf

The Wnt signaling pathway in development and disease.

The heparan sulfate on the surface of all adherent cells modulates the actions of a large number of extracellular ligands. Members of both cell surface heparan sulfate proteoglycan families, the transmembrane syndecans and the glycosylphosphoinositide-linked glypicans, bind these ligands and enhance formation of their receptor-signaling complexes. These heparan sulfate proteoglycans also immobilize and regulate the turnover of ligands that act at the cell surface. The extracellular domains of these proteoglycans can be shed from the cell surface, generating soluble heparan sulfate proteoglycans that can inhibit interactions at the cell surface. Recent analyses of genetic defects in Drosophila melanogaster, mice, and humans confirm most of these activities in vivo and identify additional processes that involve cell surface heparan sulfate proteoglycans. This chapter focuses on the mechanisms underlying these activities and on the cellular functions that they regulate.

Functions of Cell Surface Heparan Sulfate Proteoglycans

In the mammalian embryo, both sexes are initially morphologically indistinguishable: specific hormones are required for sex-specific development. Mullerian inhibiting substance and testosterone secreted by the differentiating embryonic testes result in the loss of female (Mullerian) or promotion of male (Wolffian) reproductive duct development, respectively. The signalling molecule Wnt-4 is crucial for female sexual development. At birth, sexual development in males with a mutation in Wnt-4 appears to be normal; however, Wnt-4-mutant females are masculinized—the Mullerian duct is absent while the Wolffian duct continues to develop. Wnt-4 is initially required in both sexes for formation of the Mullerian duct, then Wnt-4 in the developing ovary appears to suppress the development of Leydig cells; consequently, Wnt-4-mutant females ectopically activate testosterone biosynthesis. Wnt-4 may also be required for maintenance of the female germ line. Thus, the establishment of sexual dimorphism is under the control of both local and systemic signals.

Female development in mammals is regulated by Wnt-4 signalling

The kidney has been widely exploited as a model system for the study of tissue inductions regulating vertebrate organogenesis. Kidney development is initiated by the ingrowth of the Wolfian duct-derived ureteric bud into the presumptive kidney mesenchyme. In response to a signal from the ureter, mesenchymal cells condense, aggregate into pretubular clusters and undergo an epithelial conversion generating a simple tubule. This then undergoes morphogenesis and is transformed into the excretory system of the kidney, the nephron. We report here that the expression of Wnt-4, which encodes a secreted glycoprotein, correlates with, and is required for, kidney tubulogenesis. Mice lacking Wnt-4 activity fail to form pretubular cell aggregates; however, other aspects of mesenchymal and ureteric development are unaffected. Thus, Wnt-4 appears to act as an autoinducer of the mesenchyme to epithelial transition that underlies nephron development.

Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4.

Identification of BMP-4 as a signal mediating secondary induction between epithelial and mesenchymal tissues during early tooth development

Development of the mammalian kidney is initiated by ingrowth of the ureteric bud into the metanephric blastema. In response to signal(s) from the ureter, mesenchymal cells condense, aggregate into pretubular clusters, and undergo epithelialisation to form simple epithelial tubules. Subsequent morphogenesis and differentiation of the tubular epithelium lead to the establishment of a functional nephron. Here we demonstrate that Wnt-4, a secreted glycoprotein which is required for tubule formation, is sufficient to trigger tubulogenesis in isolated metanephric mesenchyme, whereas Wnt-11 which is expressed in the tip of the growing ureter is not. Wnt-4 signaling depends on cell contact and sulphated glycosaminoglycans and is only required for triggering tubulogenesis but not for later events. The Wnt-4 signal can be replaced by other members of the Wnt gene family including Wnt-1, Wnt-3a, Wnt-7a and Wnt-7b. Further, dorsal spinal cord, which has been thought to mimic ureteric signaling in tubule induction induces Wnt-4 mutant as well as wild-type mesenchyme suggesting that spinal cord derived signal(s) most likely act by mimicking the normal mesenchymal action of Wnt-4. These results lend additional support to the notion that Wnt-4 is a key auto-regulator of the mesenchymal to epithelial transformation that underpins nephrogenesis adding another level of complexity in the hierarchy of molecular events mediating tubulogenesis.

Wnt-4 is a mesenchymal signal for epithelial transformation of metanephric mesenchyme in the developing kidney

Reciprocal cell-cell interactions between the ureteric epithelium and the metanephric mesenchyme are needed to drive growth and differentiation of the embryonic kidney to completion. Branching morphogenesis of the Wolffian duct derived ureteric bud is integral in the generation of ureteric tips and the elaboration of the collecting duct system. Wnt11, a member of the Wnt superfamily of secreted glycoproteins, which have important regulatory functions during vertebrate embryonic development, is specifically expressed in the tips of the branching ureteric epithelium. In this work, we explore the role of Wnt11 in ureteric branching and use a targeted mutation of the Wnt11 locus as an entrance point into investigating the genetic control of collecting duct morphogenesis. Mutation of the Wnt11 gene results in ureteric branching morphogenesis defects and consequent kidney hypoplasia in newborn mice. Wnt11 functions, in part, by maintaining normal expression levels of the gene encoding glial cell-derived neurotrophic factor (Gdnf). Gdnf encodes a mesenchymally produced ligand for the Ret tyrosine kinase receptor that is crucial for normal ureteric branching. Conversely, Wnt11 expression is reduced in the absence of Ret/Gdnf signaling. Consistent with the idea that reciprocal interaction between Wnt11 and Ret/Gdnf regulates the branching process, Wnt11 and Ret mutations synergistically interact in ureteric branching morphogenesis. Based on these observations, we conclude that Wnt11 and Ret/Gdnf cooperate in a positive autoregulatory feedback loop to coordinate ureteric branching by maintaining an appropriate balance of Wnt11-expressing ureteric epithelium and Gdnf-expressing mesenchyme to ensure continued metanephric development.

Seppo Vainio

Papers

Female development in mammals is regulated by Wnt-4 signalling

Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4.

Identification of BMP-4 as a signal mediating secondary induction between epithelial and mesenchymal tissues during early tooth development

Wnt-4 is a mesenchymal signal for epithelial transformation of metanephric mesenchyme in the developing kidney

Wnt11 and Ret/Gdnf pathways cooperate in regulating ureteric branching during metanephric kidney development.