Role of the renin-angiotensin system in the development of the ureteric bud and renal collecting system

Genetic, biochemical and physiological studies have demonstrated that the renin-angiotensin system (RAS) plays a fundamental role in kidney development. All of the components of the RAS are expressed in the metanephros. Mutations in the genes encoding components of the RAS in mice or pharmacological inhibition of RAS in animals or humans cause diverse congenital abnormalities of the kidney and lower urinary tract. The latter include renal vascular abnormalities, abnormal glomerulogenesis, renal papillary hypoplasia, hydronephrosis, aberrant UB budding, duplicated collecting system, and urinary concentrating defect. Thus, the actions of angiotensin (ANG) II during kidney development are pleiotropic both spatially and temporally. Whereas the role of ANG II in renovascular and glomerular development has received much attention, little is known about the potential role of ANG II and its receptors in the morphogenesis of the collecting system. In this review, we discuss recent genetic and functional evidence gathered from transgenic knockout mice and in vitro organ and cell culture implicating the RAS in the development of the ureteric bud and collecting ducts. A novel conceptual framework has emerged from this body of work which states that stroma-derived ANG II elicits activation of AT₁/AT₂ receptors expressed on the ureteric bud to stimulate branching morphogenesis as well as collecting duct elongation and papillogenesis.     

Contact guidance in human dermal fibroblasts is modulated by population pressure

Morphogenesis is underpinned by orientated cell division, motility and growth. The substratum for migrating cells in vivo comprises either extracellular matrix or the surfaces of adjacent cells and both are believed to inform the dynamic behaviour of adherent cells through contact guidance. Collisions between migrating cells in vitro can induce the phenomena of contact inhibition of locomotion and division, suggesting that their sensitivity to substratum-derived cues may also be influenced by population density. In the present study dermal fibroblasts, which are known to be motile in culture and are fundamental to the organization of the extracellular matrix, were used to examine the influence of population pressure on the ability of substratum topography to induce contact guidance. The findings suggest that sensitivity to substratum-derived morphogenetic guidance cues, as revealed by alignment of cells to microtopography, is modulated by population pressure.     

The morphogenesis of adenocarcinoma of the cervix—a complex pathological entity

The cytological and histological features of 20 cases of adenocarcinoma of the cervix are presented of which 14 cases were in situ and two were microinvasive. The frequent association of atypia with malignancies of the cervical squamous epithelium is stressed. Abnormal reserve or stem cells were found in many of these cases. This study demonstrates the importance of the proper identification of these cells in cytological material and gives support to the theory that these cells play a role as a precursor cell to squamous and glandular neoplasms.     

Loss of PNA staining in mouse aortico-pulmonary septum is associated with mesenchymal cell apoptosis

Massive apoptosis of mesenchymal cells in the septum of the aortico-pulmonary trunk was found in mouse fetuses at stage 14.5 dpc. It was associated with the appearance of cavities in the mesenchymal tissue, presumably due to cell loss, a strong reduction in the extent of lectin PNA staining, and the induction of metallothioneins in specialized mesenchymal cells. Cell loss was spatially restricted to an inner area of the septum and was due to a distinct apoptotic pattern of cells, different from that in the heart wall. These events led to a rapid reduction of the aortico-pulmonary septum as occurs during the late stages of heart morphogenesis. It coincided with the migration of other cell types that invaded the cell-depleted septum, and contributed to the histiogenesis of the mature heart.     

GABAergic signaling in the developing cerebellum

In the adult central nervous system (CNS), GABA is a predominant inhibitory neurotransmitter that regulates glutamatergic activity. Recent studies have revealed that GABA serves as an excitatory transmitter in the immature CNS and acts as a trophic factor for brain development. Furthermore, synaptic transmission by GABA is also involved in the expression of higher brain functions, such as memory, learning and anxiety. These results indicate that GABA plays various roles in the expression of brain functions and GABAergic roles change developmentally in accordance with alterations in GABAergic transmission and signaling. We have investigated morphologically the developmental changes in the GABAergic transmission system and the key factors important for the formation of GABAergic synapses and networks using the mouse cerebellum, which provides an ideal system for the investigation of brain development. Here, we focus on GABA and GABA(A) receptors in the developing cerebellum and address the processes of how GABA exerts its effect on developing neurons and the mechanisms underlying the formation of functional GABAergic synapses.     

Histogenesis and morphogenesis of depressed-type early colorectal carcinoma

The aim of this study was to elucidate the histogenesis and morphogenesis of depressed-type early colorectal carcinomas (DECas). Eighty-seven DECas were selected for examination. The 87 DECas included 23 (26.4%) absolutely depressed (ABS) types (depressed mucosa being thinner than the normal mucosa; histologically true depression), 40 (46.0%) relatively depressed (REL) types (the thickness of the depressed mucosa being the same or greater than that of normal mucosa, with depression being relative compared to marginal elevation) and 24 (27.6%) ulcerated (UL) types (no remnant intramucosal component in the depressed area). The rates of residual adenomatous components were 0/23 (0%) for ABS type and 12/40 (30%) for REL type, indicating that the ABS type was thought to have arisen de novo and the REL type was thought to have arisen de novo and via an adenoma-carcinoma sequence. In 13 of the 23 (56.5%) ABS types, carcinoma was located within the depressed area alone, suggesting that many ABS types show a depression from their initial stage. While 33 of the 40 (82.5%) REL types accompanied by marginal elevation consisted of neoplastic mucosa, in 19 of the 33 (57.6%) cases, the depressed area showed a higher grade of atypia than the area of marginal elevation. This suggested that the depression in the REL type was generated secondarily at the center of a pre-existing, superficially elevated tumor due to progression of its histological grade of atypia. ABS type was speculated to be the precursor of UL type since the two types showed similarity (no statistical significant difference) in percent depression (69.6 vs 64.3%), grade of atypia of carcinoma (52.2 and 79.2% consisted of carcinoma with high-grade atypia alone), and frequency of being accompanied by non-neoplastic reactive marginal elevation (56.5 vs 70.8%).     

Anthrax toxin receptor proteins

Anthrax toxin is a key virulence factor for Bacillus anthracis, the causative agent of anthrax. Here we discuss what is known about the anthrax toxin receptor (ATR), the cellular receptor for anthrax toxin, and how this information is being used to develop treatments for anthrax as well as to understand aspects of cancer. ATR was identified recently as a type I transmembrane protein with unknown function that contains an extracellular integrin-like inserted (I) domain. The ATR I domain contains the toxin binding site, and a soluble form of this domain was shown to serve as an effective antitoxin to protect cultured cells from toxin action. ATR is encoded by the tumor endothelial marker 8 (TEM8) gene, which is selectively up-regulated during blood vessel formation and in tumor vasculature, raising the possibility that this protein normally functions in angiogenesis. Therefore, identification of the cellular receptor for anthrax toxin has made possible new avenues of research in the areas of anthrax pathogenesis, antitoxin development, and cancer biology.     

Form and Function: A Neuronal Dialog

The emergence of functional maturity in the brain relies upon the interplay between form and function during its developmental history. This interaction continues throughout life and changes in neuronal function lead to changes in diverse structural scales in the brain. Both regulatory genes, which define compartments in the nervous system, and activity-dependent processes cooperate to determine neuronal phenotype and tissue structure. The influence of electrical activity as a regulator of early developmental events such as proliferation and migration is being considered. Spontaneous neuronal activity may influence early axonal and dendritic arbor formation and activity blockade alters branch density both for axon arbors and dendrites. Although large-scale changes in axon morphology may occur until late stages of development, the remodeling of axon and dendrite morphology in terms of their terminal arborization area is less pronounced than initially thought. Electrical (or neural) activity is important for synapse stabilization and circuit formation and sensory experience performs a refinement of neuronal shape. This fine-tuning appears to be a dynamical process sustained into adulthood, with smaller scale changes occurring mainly at the dendritic spine level. These subcellular compartments are now believed to restrict biochemical changes in dendrites to particular synapses during (or undergoing) synaptic plasticity. Events at dendritic spines underlie alterations in the morphology of individual neurons that will ultimately affect the function of complex neuronal networks.     

Integrins in Mammary Gland Development and Differentiation of Mammary Epithelium

Integrins are major extracellular matrix (ECM) receptors that can also serve for some cell-cell interactions. They have been identified as important regulators of mammary epithelial cell growth and differentiation. Their ability to promote cell anchorage, proliferation, survival, migration, and the induction of active ECM-degrading enzymes suggests that they play an essential role in normal mammary morphogenesis, but, on the other hand, reveals their potential to promote tumor progression.