The role of growth factors in the embryogenesis and differentiation of the eye.

The vertebrate eye is composed of a variety of tissues that, embryonically, have their derivation from surface ectoderm, neural ectoderm, neural crest, and mesodermal mesenchyme. During development, these different types of cells are subjected to complex processes of induction and suppressive interactions that bring about their final differentiation and arrangement in the fully formed eye. With the changing concept of ocular development, we present a new perspective on the control of morphogenesis at the cellular and molecular levels by growth factors that include fibroblast growth factors, epidermal growth factor, nerve growth factor, platelet-derived growth factor, transforming growth factors, mesodermal growth factors, transferrin, tumor necrosis factor, neuronotrophic factors, angiogenic factors, and antiangiogenic factors. Growth factors, especially transforming growth factor-beta, have a crucial role in directing the migration and developmental patterns of the cranial neural-crest cells that contribute extensively to the structures of the eye. Some growth factors also exert an effect on the developing ocular tissues by influencing the synthesis and degradation of the extracellular matrix. The mRNAs for the growth factors that are involved in the earliest aspects of the growth and differentiation of the fertilized egg are supplied from maternal sources until embryonic tissues are able to synthesize them. Subsequently, the developing eye tissues are exposed to both endogenous and exogenous growth factors that are derived from nonocular tissues as well as from embryonic fluids and the systemic circulation. The early interaction between the surface head ectoderm and the underlying chordamesoderm confers a lens-forming bias on the ectoderm; later, the optic vesicle elicits the final phase of determination and enhances differentiation by the lens. After the blood-ocular barrier is established, the internal milieu of the eye is controlled by the interactions among the intraocular tissues; only those growth factors that selectively cross the barrier or that are synthesized by the ocular tissues can influence further development and differentiation of the cells. An understanding of the tissue interactions that are regulated by growth factors could clarify the precise mechanism of normal and abnormal ocular development.     

Intrinsic and extrinsic control of growth in developing organs

The growth rate and final size of developing organs is controlled by organ-intrinsic mechanisms as well as by hormones and growth factors that originate outside the target organ. Recent work on Drosophila imagined discs and other regenerating systems has led to the conclusion that the intrinsic growth-control mechanism that controls regenerative growth depends on position-specific interactions between cells and their neighbors, and that these interactions also control pattern formation. According to this interpretation, local growth by cell proliferation is stimulated when cells with disparate positional information are confronted as a result of grafting or wound healing. This local growth leads to intercalation of cells with intervening positional values until the positional information discontinuity is eliminated. When all discontinuities have been eliminated from a positional field, growth stops. In this article we consider the possibility that organ growth during normal development may be controlled by an intercalation mechanism similar to that proposed for regenerative growth. Studies of imaginal disc growth are consistent with this suggestion, and in addition they show that the cell interactions thought to control growth are independent of cell lineage. Developing organs of vertebrates also show intrinsic growth-control mechanisms, as demonstrated by the execution of normal growth programs by immature organs that are transplanted to fully grown hosts or to hosts with genetically different growth parameters. Furthermore, these organ-intrinsic mechanisms also appear to be based on position-specific cell interactions, as suggested by the growth stimulation seen after partial extirpation or rearrangement by grafting. In organs of most adult vertebrates, the organ-intrinsic growth-control system seems to be suppressed as shown by the loss of regenerative ability, although it is clearly retained in the limbs, tails and other organs of salamanders. The clearest example of an extrinsic growth regulator is growth hormone, which plays a dominant role along with insulin-like growth factors, thyroid hormone and sex hormones in supporting the growth of bones and other organs in postnatal mammals. These hormones do not appear to regulate prenatal growth, but other hormones and insulin-like growth factors may be important prenatally. The importance of other growth factors in regulating organ growth in vivo remains to be established. It is argued that both intrinsic and extrinsic factors control organ growth, and that there may be important interactions between the two types of control during development.     

On microbial states of growth†

It is crucial to the reproducibility of results and their proper interpretation that the conditions under which experiments are carried out be defined with rigour and consistency, in this review we attempt to clarify the differences and interrelationships among steady, balanced and exponential states of culture growth. Basic thermodynamic concepts are used to introduce the idea of steady-state growth in open, biological systems. The classical, sometimes conflicting, definitions of steady-state and balanced growth are presented, and a consistent terminology is proposed. The conditions under which a culture in balanced growth is also in exponential growth and in steady-state growth are indicated. It is pointed out that steady-state growth always implies both balanced and exponential growth, and examples in which the converse does not hold are described. More complex situations are then characterized and the terminology extended accordingly. This leads to the notion of normal growth and growth that can be synchronous or otherwise unbalanced but still reproducible, and to the condition of approximate steady state manifested by growth in batch culture and by asymmetrically dividing cells, which is analysed in some detail.     

Mechanical effects on skeletal growth

The growth (i.e. increase of external dimensions) of long bones and vertebrae occurs longitudinally by endochondral ossification at the growth plates, and radially by apposition of bone at the periosteum. It is thought that mechanical loading influences the rate of longitudinal growth. The 'Hueter-Volkmann Law' proposes that growth is retarded by increased mechanical compression, and accelerated by reduced loading in comparison with normal values. The present understanding of this mechanism of bone growth modulation comes from a combination of clinical observation (where altered loading and growth is implicated in some skeletal deformities) and animal experiments in which growth plates of growing animals have been loaded. The gross effect of growth modulation has been demonstrated qualitatively and semi-quantitatively. Sustained compression of physiological magnitude inhibits growth by 40% or more. Distraction increases growth rate by a much smaller amount. Experimental studies are underway to determine how data from animal studies can be scaled to other growth plates. Variables include: differing sizes of growth plate, different anatomical locations, different species and variable growth rate at different stages of skeletal maturity. The two major determinants of longitudinal growth are the rate of chondrocytic proliferation and the amount of chondrocytic enlargement (hypertrophy) in the growth direction. It is largely unknown what are the relative changes in these key variables in mechanically modulated growth, and what are the signaling pathways that produce these changes.     

Modeling pollen tube growth: Feeling the pressure to deliver testifiable predictions

The frequency and amplitude of oscillatory pollen tube growth can be altered by changing the osmotic value of the surrounding medium. This has motivated the proposition that the periodic change in growth velocity is caused by changes in turgor pressure. Using mathematical modeling we recently demonstrated that the oscillatory pollen tube growth does not require turgor to change but that this behavior can be explained with a mechanism that relies on changes in the mechanical properties of the cell wall which in turn are caused by temporal variations in the secretion of cell wall precursors. The model also explains why turgor and growth rate are correlated for oscillatory growth with long growth cycles while they seem uncorrelated for oscillatory growth with short growth cycles. The predictions made by the model are testifiable by experimental data and therefore represent an important step towards understanding the dynamics of the growth behavior in walled cells.     

The coordination of growth among Drosophila organs in response to localized growth-perturbation

The developmental mechanisms by which growth is coordinated among developing organs are largely unknown and yet are essential to generate a correctly proportioned adult. In particular, such coordinating mechanisms must be able to accommodate perturbations in the growth of individual organs caused by environmental or developmental stress. By autonomously slowing the growth of the developing wing discs within Drosophila larvae, we show that growing organs are able to signal localized growth perturbation to the other organs in the body and slow their growth also. Growth rate is so tightly coordinated among organs that they all show approximately the same reduction in growth rate as the developing wings, thereby maintaining their correct size relationship relative to one another throughout development. Further, we show that the systemic growth effects of localized growth-perturbation are mediated by ecdysone. Application of ecdysone to larvae with growth-perturbed wing discs rescues the growth rate of other organs in the body, indicating that ecdysone is limiting for their growth, and disrupts the coordination of their growth with growth of the wing discs. Collectively our data demonstrate the existence of a novel growth-coordinating mechanism in Drosophila that synchronizes growth among organs in response to localized growth perturbation.     

Embryonal carcinoma cell growth and differentiation. Production of and response to molecules with transforming growth factor activity

Transforming growth factors are known to induce anchorage-independent growth of non-transformed cells, and are released by a variety of cells, including MSV-transformed cells. This study demonstrates that the differentiated cells derived from F9 and PC-13 embryonal carcinoma cells, but not the parental cells themselves, respond by increased growth to several factors released by MSV-transformed cells, including partially purified sarcoma growth factor. The chemical properties of the growth-promoting activity are shown to match the chemical properties of the transforming growth factors released by MSV-transformed cells. Furthermore, F9 and PC-13 embryonal carcinoma cells, which do not respond to factors released by MSV-transformed cells, are shown to release factors with transforming growth factor activity. Based on the close relationship between mouse embryonal carcinoma cells and cells of early mouse embryos, it is suggested that molecules with transforming growth factor activity may play a role during the early stages of mammalian development.     

Growth patterns of Lower Palaeozoic sponges

Detailed studies of the growth patterns of modern siliceous sponges are restricted to demosponges and theoretical models. It is generally assumed that sponge growth is essentially incremental, with completion of one arbitrary unit being followed by external addition. All recent species are thick-walled, but Lower Palaeozoic sponges are dominated by thin-walled hexactinellids, with most Cambrian taxa consisting of a single spicule layer. Large populations of a primitive dictyospongiid have allowed the reconstruction of the growth patterns of their spicules and body morphology. The results indicate that growth occurred through continuous expansion of the globose body, accompanied by continuous enlargement of existing spicules, with a spicule size limit being reached only during the lifetime of a few individuals. It is noted that this skeletal growth pattern is otherwise restricted to deuterostomes. Consecutive appearance of successive spicule size orders appears to have maintained a maximum inhalant pore area. Comparisons with more limited data from two acanthose hexactinellids and a hazeliid demosponge indicate that an identical growth pattern operated in these species. The subsequent evolution of growth patterns is discussed, with various mechanisms producing the later thick-walled morphologies of hexactinellids and demosponges. The implications of these observations are discussed with reference to identification and systematics, since spicule size and arrangement are shown to vary during growth.     

Cellular responsiveness to growth factors correlates with a cell's ability to express the transformed phenotype

Five random subclones of the rat fibroblast line F2408 vary in their frequency of transformation by the unrelated Kirsten murine sarcoma virus and Abelson murine leukemia virus. The same pattern of sensitivity is displayed when the cells are induced to anchorage-independent growth (transformed) by epidermal, platelet-derived, and sarcoma growth factors, or by whole serum. Our results demonstrate that a growth factor's ability to render cells anchorage independent is not unique to transforming growth factors, but common to many growth factors; anchorage-independent growth is a function of the total growth factor concentration in the medium; cells vary in their inherent responsiveness to growth-factor-induced anchorage-independent growth; and cells resistant to growth-factor-induced anchorage-independent growth are also resistant to transformation by a variety of tumor viruses. We conclude that the way a cell responds to growth factors plays a central role in the expression of the transformed phenotype.     

Loss of insulin-like growth factor II receptor expression promotes growth in cancer by increasing intracellular signaling from both IGF-I and insulin receptors

The insulin-like growth factor-II receptor (IGF-IIR) is frequently mutated or deleted in some malignant human tumors, suggesting that the IGF-IIR is a tumor suppressor. However, the exact mechanism by which IGF-IIR suppresses growth in tumors has not been definitively established. We demonstrate that IGF-IIR-deficient murine L cells (D9) have higher growth rates than IGF-IIR-positive L cells (Cc2) in response to IGF-II. IGF-II levels are higher in growth-conditioned medium from D9 versus Cc2 cells. Receptor neutralization studies and measurements of insulin receptor substrate 1 phosphorylation confirm that the enhanced growth of D9 cells is due to increased stimulation of the IGF-I and insulin receptors by IGF-II. In contrast, the levels of secreted latent and active transforming growth factor beta (TGF-beta) are similar for both D9 and Cc2 cells, indicating that the slower growth of Cc2 cells is not due to activation of latent TGF-beta by IGF-IIR and growth inhibition. The results directly demonstrate that down regulation of the IGF-IIR promotes the growth of transformed D9 cells by sustaining IGF-II, which binds to and activates IGF-IR and insulin receptor to increase intracellular growth signals.     

Growth patterns in euconodont crown enamel: implications for life history and mode-of-life reconstruction in the earliest vertebrates

Euconodonts were the first vertebrates to produce a mineralized skeleton. It is concluded that the minor increments in the crown enamels of Protopanderodus varicostatus and Drepanodus robustus are probable homologues of the cross striations in hominoid enamel, although they are much more variable in thickness and represent daily to weekly growth. Major increments are superficially similar to lines of Retzuis, but represent a check in growth that is likely to have occurred at monthly intervals. Periods of above- and below-average growth are likely to have been seasonally moderated. The growth of P. varicostatus' elements are characterized by two distinct phases: the production of a triangular, asymmetrical juvenile 'proto-element' followed, in a second phase, by the development of the curved and twisted geometry of the adult element. These fundamentally different morphologies imply that juvenile and adult animals had different modes of life and/or feeding strategies. In these animals the growth of the elements was indeterminate. The growth model for euconodonts is clearly different from that of hominoid teeth as the enamel organ must have reformed repeatedly throughout life.     

Evolution of human growth spurts

This study investigates subadult growth spurts in a large sample of anthropoid primates, including humans. Analyses of body mass growth curves show that humans are not unique in the expression of female and male body mass growth spurts. Subadult growth spurts are observed in both New World and Old World anthropoid primates and are more common in males than in females. Allometric analyses of growth spurts indicate that many aspects of primate growth spurts are strongly correlated with species size. Small species tend not to exhibit growth spurts. Although male and female scaling patterns for velocity and size measures are comparable, scaling relations of variables that measure the timing of growth spurts differ by sex. These patterns can he related to sexual differences in life histories. Scaling analyses further show that humans do not depart substantially from patterns that describe other anthropoid primates. Thus, in relative terms, human growth spurts are not exceptional compared to this sample of primates. The long absolute delay in the initiation of the human growth spurt may be of substantial evolutionary importance and serves to distinguish humans from other primates. In essence, humans exhibit growth spurts that are comparable to other primates in many respects. However, human growth spurts are shifted to very late absolute ages. © 1996 Wiley-Liss, Inc.     

Prenatal growth pattern of the human maxilla.

Regarding maxillofacial morphogenesis there has been a long debate on the growth of the maxillary structure. Using 120 normal fetal maxillae of gestational ages from 16 to 41 weeks, palatal radiograms and frontal histologic sections were made. We have observed two pairs of accentuated growth areas in the fetal maxillae and named them primary growth centers to formulate the maxillary trapezoid (MT) by radiologic image. The MT is formed by four primary growth centers that are best demonstrated by palatal radiograms of the fetal maxilla as well as by frontal histologic sections. The dimensional increase in the MT during the fetal period is documented and statistically analyzed. From this series of results, we have suggested that the growth centers which demarcate the MT are the basic structures of the developing human maxilla. It was also found that the four primary growth centers are the most active sites for maxilla formation until 20 weeks of gestation and thereafter the growth of the maxilla is enhanced by the participation of the intramembranous bone formation along the periphery. This was in contrast to the central primary growth centers that have already finished maturation in the early fetal period and remain only as a peripherally radiating arrangement of thick trabecular bones.     

Morphology and anatomy in annual taxa of Beta vulgaris s.l. (Chenopodiaceae)

Beta vulgaris s.l. is a morphologically variable taxon, that has transitional growth types between strictly orthotropous and plagiotropous growth. The development of a "secondary branching system" at the end of the growing season in taxa that are summer annual (under the climatic conditions of Central Germany) leads to perennial taxa that form slender storage roots and overwinter as rosettes. The shoots of the four morphologically different annual taxa are very similar anatomically. Collenchymatous ridges, that are conspicuous macroscopically as stem ridges, are typical. The secondary growth is anomalous and often irregular. Six more or less complete rings of connective and vascular tissue are formed in the roots by successively arising cambia, which have an unlimited ability to divide. However, the diameter of the roots does not only enlarge by divisions within the cambia but also by primary growth within the connective tissue.     

The relative contributions of changes in yield and land area to increasing crop output

Global average yields of the world's main food crops have increased over the past 50 years, and these yield increases have varied over time. For most crops, yields have grown significantly faster during periods of higher demand growth, and the contribution of yield growth to output growth has varied between crops. These variations reflect the range of measures available to growers to enhance yields of each crop, which are typically not fully deployed during periods of low demand growth and low relative price. This paper applies two methods using consistent, long‐term historic relationships to demonstrate that crop yield, area and price changes are not independent, and that area changes and yield changes in response to market signals are different for different crops and regions. One of these methods is used to show the expected percentages of exogenous estimates of overall demand growth that will be met by yield growth and by land use change for a range of biofuel crops. The estimated percentage of incremental output growth delivered by yield growth is 78% for EU cereals, with the remainder being met by area growth.     

Dynamics of cellular growth.

The assumption that prompted the studies reported in this paper was that the unsatisfactory state of our knowledge on the regulation of cellular growth might derive from the reductionistic approach used to investigate it. Thus an analysis of cellular growth which applied concepts derived from systems dynamics was undertaken. First of all a dynamic model of cellular growth has been constructed. It has the following features: the levels of DNA, ribosomes and proteins are the defining levels; cellular growth is expressed by a close loop in which the level of ribosomes per genome and, indirectly, the level of proteins per genome are stabilized around goal values by the action of negative feed backs. The validity of the model has been tested by its ability to predict the growth kinetics of a real system (exponentially growing Neurospora cells). The simulated growth has been found to reproduce with great accuracy that of Neurospora cells. A slightly modified model, which takes into consideration also the degradation of ribosomes and of proteins, is shown to predict with accuracy the dynamics of growth of both growing and resting fibroblasts. These latter results suggest that the rates of macromolecular turnovers play a central role in the control of proliferation of mammalian cells: the condition of zero growth seems to be achieved when the rate of synthesis and the rate of degradation of proteins are the same. The possibility is discussed that the model indicates a unifying hypothesis of the mode of action of growth controlling conditions (hormones, growth factors, contact inhibition).     

Rapid cellular responses to auxin and the regulation of growth

Abstract The cellular responses rapidly evoked by auxin are reviewed, and related to a consideration of how growth rate is regulated in excised segments and in whole dicotyledonous plants. Two processes, synthesis of proteins and of cell wall components, are both promoted by auxin and essential for auxin-stimulated growth, whereas other processes show little promotion by auxin or do not appear essential for growth. Current models for the cellular regulation of growth by auxin are briefly discussed, and a new model presented. Auxin is suggested to act by bringing about a transient increase in cytosolic Ca²⁺ levels, which through the stimulation of protein kinases converts a cytoplasmic protein factor to an active state capable of binding auxin. The protein-auxin complex induces mRNA synthesis, which effects the increased synthesis of cell wall components and their incorporation into the wall, resulting in wall loosening and growth. It is proposed that the factor limiting growth in floating excised segments may initially be cell wall pH, but that this is not the case in whole plants and growth is instead mediated by increased protein and matrix cell wall synthesis. Differences are noted between monocotyledonous coleoptiles and dicotyledonous stems in some metabolic processes possibly involved in auxin growth responses, and it is cautioned that observations made on one tissue may not necessarily be applicable to the other. Care should also be taken in applying conclusions drawn from studies on excised tissue to the interpretation of growth regulation in the whole plant.     

Growth cones isolated from identified Aplysia neurons in vitro: biochemical and morphological characterization

The right upper quadrant (RUQ) cells (R3-R13) of Aplysia regenerating in dissociated cell culture form unusually large growth cones. The movement of these growth cones was observed by time-lapse phase microscopy and their ultrastructure was examined by transmission electron microscopy. Their behavior and ultrastructure have features that are typical of growth cones in vitro. Additionally, they contain neurosecretory granules similar to those found in these cells in vivo. Because RUQ growth cones are large, they can be isolated by manual dissection. RUQ cells were grown in the presence of [35S]methionine and the labeled proteins transported to the growth cones were analyzed by SDS-PAGE. These proteins were compared to those in RUQ cell bodies, RUQ neurites, and to those in the neurites and cell bodies of other identified neurons grown in vitro. Most proteins synthesized by RUQ cells in vitro are transported to their growth cones, including several glycoproteins and the precursor to the R3-R14 neuropeptide. Neuropeptides are also synthesized by a number of other Aplysia neurons growing in vitro. We examined R2, LPL1, R15, and left upper quadrant neurons and found that their precursor peptides, like those of R3-R14, are readily recognized as major cell-specific radiolabeled bands on SDS gels. The presence in regenerating growth cones of neuropeptides, neurosecretory granules, and glycoproteins known to be rapidly transported toward synapses in vivo supports the emerging view that the growth cone in vitro contains not only a motility apparatus but also a macromolecular assembly capable of forming an active synapse immediately upon or shortly after contacting targets.     

A Mathematical Model for BRASSINOSTEROID INSENSITIVE1-Mediated Signaling in Root Growth and Hypocotyl Elongation

Brassinosteroid (BR) signaling is essential for plant growth and development. In Arabidopsis (Arabidopsis thaliana), BRs are perceived by the BRASSINOSTEROID INSENSITIVE1 (BRI1) receptor. Root growth and hypocotyl elongation are convenient downstream physiological outputs of BR signaling. A computational approach was employed to predict root growth solely on the basis of BRI1 receptor activity. The developed mathematical model predicts that during normal root growth, few receptors are occupied with ligand. The model faithfully predicts root growth, as observed in bri1 loss-of-function mutants. For roots, it incorporates one stimulatory and two inhibitory modules, while for hypocotyls, a single inhibitory module is sufficient. Root growth as observed when BRI1 is overexpressed can only be predicted assuming that a decrease occurred in the BRI1 half-maximum response values. Root growth appears highly sensitive to variation in BR concentration and much less to reduction in BRI1 receptor level, suggesting that regulation occurs primarily by ligand availability and biochemical activity.