Digit morphogenesis: Is the tip different?

Digit formation is the last step in the skeletal patterning of developing limbs. This process involves important aspects such as determination of chondrogenic versus interdigital areas; growth of digital rays with periodic segmentation to form joints and thus phalanges, and finally tip formation. Traditionally it was believed that the properties of digital rays were fixed at earlier stages, but recently a surprising plasticity of digit primordia at the time of condensation has been demonstrated. This implies the presence of local interactions that are able to modulate the particular programs that make a given digit, but we don't fully understand how they operate. An involvement of signaling from the interdigital spaces and from the apical ectodermal ridge has been proposed. Another interesting question is the formation of the last limb structure, digit tips, which may involve a specific molecular and cellular program. Indeed, the expression of several developmentally important genes is restricted to digit tips at late stages of limb development. Understanding the molecular and cellular interactions that lead to digit morphogenesis has important implications not only in the context of embryonic development (for example, how early cues received by cells are translated into anatomy or what are the mechanisms that control the cease of activity of signaling regions) but also in terms of limb diversification during evolution.     

Is the behaviour of the leg during oscillation linear?

The linear behaviour of the human leg was studied using a free oscillation method. The lower leg is represented by a simple mass, spring and dashpot model. Forty-five subjects underwent free vibration tests on their right legs. The force amplitude and the time period, for successive oscillations enabled calculation of the stiffness to mass ratio values. It was found that the time period of the second oscillation cycle was significantly lower than that of the first, implying a corresponding increase in stiffness. The experimental data consistently exhibits these non-linear characteristics, indicating that the use of non-linear models could be of benefit for future free oscillation studies.     

ATP-mediated cell–cell signaling in the organ of Corti: the role of connexin channels

Connexin 26 (Cx26) and connexin 30 (Cx30) form hemichannels that release ATP from the endolymphatic surface of cochlear supporting and epithelial cells and also form gap junction (GJ) channels that allow the concomitant intercellular diffusion of Ca²⁺ mobilizing second messengers. Released ATP in turn activates G-protein coupled P2Y₂ and P2Y₄ receptors, PLC-dependent generation of IP₃, release of Ca²⁺ from intracellular stores, instigating the regenerative propagation of intercellular Ca²⁺ signals (ICS). The range of ICS propagation is sensitive to the concentration of extracellular divalent cations and activity of ectonucleotidases. Here, the expression patterns of Cx26 and Cx30 were characterized in postnatal cochlear tissues obtained from mice aged between P5 and P6. The expression gradient along the longitudinal axis of the cochlea, decreasing from the basal to the apical cochlear turn (CT), was more pronounced in outer sulcus (OS) cells than in inner sulcus (IS) cells. GJ-mediated dye coupling was maximal in OS cells of the basal CT, inhibited by the nonselective connexin channel blocker carbenoxolone (CBX) and absent in hair cells. Photostimulating OS cells with caged inositol (3,4,5) tri-phosphate (IP₃) resulted in transfer of ICS in the lateral direction, from OS cells to IS cells across the hair cell region (HCR) of medial and basal CTs. ICS transfer in the opposite (medial) direction, from IS cells photostimulated with caged IP₃ to OS cells, occurred mostly in the basal CT. In addition, OS cells displayed impressive rhythmic activity with oscillations of cytosolic free Ca²⁺ concentration ([Ca²⁺]_i) coordinated by the propagation of Ca²⁺ wavefronts sweeping repeatedly through the same tissue area along the coiling axis of the cochlea. Oscillations evoked by uncaging IP₃ or by applying ATP differed greatly, by as much as one order of magnitude, in frequency and waveform rise time. ICS evoked by direct application of ATP propagated along convoluted cellular paths in the OS, which often branched and changed dynamically over time. Potential implications of these findings are discussed in the context of developmental regulation and cochlear pathophysiology.     

Wnt/β-catenin dependent cell proliferation underlies segmented lateral line morphogenesis

Morphogenesis is a fascinating but complex and incompletely understood developmental process. The sensory lateral line system consists of only a few hundred cells and is experimentally accessible making it an excellent model system to interrogate the cellular and molecular mechanisms underlying segmental morphogenesis. The posterior lateral line primordium periodically deposits prosensory organs as it migrates to the tail tip. We demonstrate that periodic proneuromast deposition is governed by a fundamentally different developmental mechanism than the classical models of developmental periodicity represented by vertebrate somitogenesis and early Drosophila development. Our analysis demonstrates that proneuromast deposition is driven by periodic lengthening of the primordium and a stable Wnt/β-catenin activation domain in the leading region of the primordium. The periodic lengthening of the primordium is controlled by Wnt/β-catenin/Fgf-dependent proliferation. Once proneuromasts are displaced into the trailing Wnt/β-catenin-free zone they are deposited. We have previously shown that Wnt/β-catenin signaling induces Fgf signaling and that interactions between these two pathways regulate primordium migration and prosensory organ formation. Therefore, by coordinating migration, prosensory organ formation and proliferation, localized activation of Wnt/β-catenin signaling in the leading zone of the primordium plays a crucial role in orchestrating lateral line morphogenesis.     

Enhanced expression of VEGF-A in β cells increases endothelial cell number but impairs islet morphogenesis and β cell proliferation

There is a reciprocal interaction between pancreatic islet cells and vascular endothelial cells (EC) in which EC-derived signals promote islet cell differentiation and islet development while islet cell-derived angiogenic factors promote EC recruitment and extensive islet vascularization. To examine the role of angiogenic factors in the coordinated development of islets and their associated vessels, we used a "tet-on" inducible system (mice expressing rat insulin promoter-reverse tetracycline activator transgene and a tet-operon-angiogenic factor transgene) to increase the β cell production of vascular endothelial growth factor-A (VEGF-A), angiopoietin-1 (Ang1), or angiopoietin-2 (Ang2) during islet cell differentiation and islet development. In VEGF-A overexpressing embryos, ECs began to accumulate around epithelial tubes residing in the central region of the developing pancreas (associated with endocrine cells) as early as embryonic day 12.5 (E12.5) and increased dramatically by E16.5. While α and β cells formed islet cell clusters in control embryos at E16.5, the increased EC population perturbed endocrine cell differentiation and islet cell clustering in VEGF-A overexpressing embryos. With continued overexpression of VEGF-A, α and β cells became scattered, remained adjacent to ductal structures, and never coalesced into islets, resulting in a reduction in β cell proliferation and β cell mass at postnatal day 1. A similar impact on islet morphology was observed when VEGF-A was overexpressed in β cells during the postnatal period. In contrast, increased expression of Ang1 or Ang2 in β cells in developing or adult islets did not alter islet differentiation, development, or morphology, but altered islet EC ultrastructure. These data indicate that (1) increased EC number does not promote, but actually impairs β cell proliferation and islet formation; (2) the level of VEGF-A production by islet endocrine cells is critical for islet vascularization during development and postnatally; (3) angiopoietin-Tie2 signaling in endothelial cells does not have a crucial role in the development or maintenance of islet vascularization.     

Mechanisms of Müller glial cell morphogenesis

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Is canavanine a natural component of mammalian metabolism?

A group of non-protein amino acids of higher plants, namely l-canavanine, l-canaline, 0-ureido-l-homoserine, and l-canavaninosuccinic acid, have been implicated in mammalian intermediary metabolism. The clinical observations and biochemical basis for this hypothesis as well as conflicting experimental evidence are presented. A possible explanation for the apparent role of these non-protein amino acids in mammalian metabolism is offered.     

Is the surface area of the red cell membrane skeleton locally conserved?

The incompressibility of the lipid bilayer keeps the total surface area of the red cell membrane constant. Local conservation of membrane surface area requires that each surface element of the membrane skeleton keeps its area when its aspect ratio is changed. A change in area would require a flow of lipids past the intrinsic proteins to which the skeleton is anchored. in fast red cell deformations, there is no time for such a flow. Consequently, the bilayer provides for local area conservation. In quasistatic deformations, the extent of local change in surface area is the smaller the larger the isotropic modulus of the skeleton in relation to the shear modulus. Estimates indicate: (a) the velocity of relative flow between lipid and intrinsic proteins is proportional to the gradient in normal tension within the skeleton and inversely proportional to the viscosity of the bilayer; (b) lateral diffusion of lipids is much slower than this flow; (c) membrane tanktreading at frequencies prevailing in vivo as well as the release of a membrane tongue from a micropipette are fast deformations; and (d) the slow phase in micropipette aspiration may be dominated by a local change in skeleton surface.     

What is the extent of prokaryotic diversity?

The extent of microbial diversity is an intrinsically fascinating subject of profound practical importance. The term 'diversity' may allude to the number of taxa or species richness as well as their relative abundance. There is uncertainty about both, primarily because sample sizes are too small. Non-parametric diversity estimators make gross underestimates if used with small sample sizes on unevenly distributed communities. One can make richness estimates over many scales using small samples by assuming a species/taxa-abundance distribution. However, no one knows what the underlying taxa-abundance distributions are for bacterial communities. Latterly, diversity has been estimated by fitting data from gene clone libraries and extrapolating from this to taxa-abundance curves to estimate richness. However, since sample sizes are small, we cannot be sure that such samples are representative of the community from which they were drawn. It is however possible to formulate, and calibrate, models that predict the diversity of local communities and of samples drawn from that local community. The calibration of such models suggests that migration rates are small and decrease as the community gets larger. The preliminary predictions of the model are qualitatively consistent with the patterns seen in clone libraries in 'real life'. The validation of this model is also confounded by small sample sizes. However, if such models were properly validated, they could form invaluable tools for the prediction of microbial diversity and a basis for the systematic exploration of microbial diversity on the planet.     

Is there an estrogenic component in the metabolic syndrome?

One of the major upcoming concerns leading to health related problems in the industrialized societies is the metabolic syndrome which is characterized by central obesity, hypertension, raised fasting glucose and triglyceride levels. The focus of this review is on a potential estrogenic linkage between the metabolic mechanisms involved into the development of this disease cluster and specific estrogen related regulatory pattern. The candidate molecules for this link are insulin and insulin-like growthfactor, C-reactive protein, peroxisome-proliferation-activatingreceptorgamma, and leptin which all seem to interact with each other and show a responsiveness to changing estrogen levels. From this perspective they might also represent target molecules for a phytochemical intervention with phytoestrogens.