The formation of cartilage elements in the developing vertebrate limb, where they serve as primordia for the appendicular skeleton, is preceded by the appearance of discrete cellular condensations. Control of the size and spacing of these condensations is a key aspect of skeletal pattern formation. Limb bud cell cultures grown in the absence of ectoderm formed continuous sheet-like masses of cartilage. With the inclusion of ectoderm, these cultures produced one or more cartilage nodules surrounded by zones of noncartilaginous mesenchyme. Ectodermal fibroblast growth factors (FGF2 and FGF8), but not a mesodermal FGF (FGF7), substituted for ectoderm in inhibiting chondrogenic gene expression, with some combinations of the two ectodermal factors leading to well-spaced cartilage nodules of relatively uniform size. Treatment of cultures with SU5402, an inhibitor FGF receptor tyrosine kinase activity, rendered FGFs ineffective in inducing perinodular inhibition. Inhibition of production of FGF receptor 2 (FGFR2) by transfection of wing and leg cell cultures with antisense oligodeoxynucleotides blocked appearance of ectoderm- or FGF-induced zones of perinodular inhibition of chondrogenesis and, when introduced into the limb buds of developing embryos, led to shorter, thicker, and fused cartilage elements. Because FGFR2 is expressed mainly at sites of precartilage condensation during limb development in vivo and in vitro, these results suggest that activation of FGFR2 by FGFs during development elicits a lateral inhibitor of chondrogenesis that limits the expansion of developing skeletal elements.
We present a stochastic cellular automaton model for the behavior of limb bud precartilage mesenchymal cells undergoing chondrogenic patterning. This "agent-oriented" model represents cells by points on a lattice that obey rules motivated by experimental findings. The "cells" follow these rules as autonomous agents, interacting with other cells and with the microenvironments cell activities produce. The rules include random cell motion, production and lateral deposition of a substrate adhesion molecule (SAM, corresponding to fibronectin), production and release of a diffusible growth factor ("activator," corresponding to TGF-beta) that stimulates production of the SAM, and another diffusible factor ("inhibitor") that suppresses the activity of the activator. We implemented the cellular automaton on a two-dimensional (2D) square lattice to emulate the quasi-2D micromass culture extensively used to study patterning in avian limb bud precartilage cells. We identified parameters that produce nodular patterns that resemble, in size and distribution, cell condensations in leg-cell cultures, thus establishing a correspondence between in vitro and in silico results. We then studied the in vitro and in silico micromass cultures experimentally. We altered the standard in vitro micromass culture by diluting the initial cell density, transiently exposing it to exogenous activator, suppressing the inhibitor, and constitutively activating fibronectin production. We altered the standard in silico micromass culture in each case by changing the corresponding parameter. In vitro and in silico experiments agreed well. We also used the model to test hypotheses for differences in the in vitro patterns of cells derived from chick embryo forelimb and hindlimb. We discuss the applicability of this model to limb development in vivo and to other organ development.
In plants with alternately arranged foliage, such as the coconut palm (Cocos nucifera), leaves are attached to the stem in either an ascending clockwise (left handed [L]) or counterclockwise (right handed [R]) spiral (Fig. 1). Foliar spiral direction (FSD) is not genetically determined in coconut palms: All crosses (R 3 R, R 3 L, L 3 R, L 3 L) yield R and L progeny in approximately equal numbers (Davis, 1962;Louis and Chidambaram, 1976;Toar et al., 1979). FSD is, thus, a classic case of morphological asymmetry in which dextral and sinistral forms are not inherited and are equally common within a species (Palmer, 2005). FSD would seem a simple stochastic process unworthy of further study if not for the observation by T.A. Davis, based on data collected from over 70,000 coconut palms in over 40 locations around the world, that the FSD of coconut palms varies with latitude: R trees predominate in the northern hemisphere and L trees predominate in the southern hemisphere (Davis and Davis, 1987). A reanalysis of Davis's data indicated that these hemispheric asymmetries in FSD are significantly better correlated with magnetic (dip) latitude than with geographic or geomagnetic (centered dipole) latitude, suggesting that latitudinal asymmetries in FSD might be associated with the temporally varying component of the Earth's magnetic field (Minorsky, 1998). Here, we report that asymmetries in FSD are also evident in populations of coconut palms on opposite sides of islands and that asymmetries between cohorts vary with an 11-year periodicity-two novel discoveries consistent with the hypothesis that geomagnetic variations underlie asymmetries in coconut palm FSD.Whereas the effects of the geomagnetic field on the orientation of magnetotactic bacteria and various animals, particularly insects and migratory birds, has been extensively studied, relatively little is known about the effects of geomagnetism on plants (Belyavskaya, 2004; Galland and Pazur, 2005). Important questions remain unanswered, such as whether or not plants perceive the geomagnetic field and, if they do, by what mechanisms and to what possible advantage, if any? At this early stage in our understanding of magnetoreception, several alternative mechanisms are being discussed by biophysicists concerning how cells might sense weak electromagnetic fields. Among the proposed modes of action are (1) torque on ferromagnetic particles; (2) modulation of biochemical reactions that involve spin-correlated radical pairs (radical-pair mechanism); (3) modulation of the transport rates and binding by ion-cyclotron resonance; and (4) quantum coherence mechanisms (for review, see Galland and Pazur, 2005). Regardless of the exact mechanisms involved in the physical reception of magnetic stimulation, considerable evidence suggests the involvement of biological membranes, in general (Balcavage et al.
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