Hormonal regulation of fetal growth

Fetal growth is a complex process depending on the genetics of the fetus, the availability of nutrients and oxygen to the fetus, maternal nutrition and various growth factors and hormones of maternal, fetal and placental origin. Hormones play a central role in regulating fetal growth and development. They act as maturational and nutritional signals in utero and control tissue development and differentiation according to the prevailing environmental conditions in the fetus. The insulin-like growth factor (IGF) system, and IGF-I and IGF-II in particular, plays a critical role in fetal and placental growth throughout gestation. Disruption of the IGF1, IGF2 or IGF1R gene retards fetal growth, whereas disruption of IGF2R or overexpression of IGF2 enhances fetal growth. IGF-I stimulates fetal growth when nutrients are available, thereby ensuring that fetal growth is appropriate for the nutrient supply. The production of IGF-I is particularly sensitive to undernutrition. IGF-II plays a key role in placental growth and nutrient transfer. Several key hormone genes involved in embryonic and fetal growth are imprinted. Disruption of this imprinting causes disorders involving growth defects, such as Beckwith-Wiedemann syndrome, which is associated with fetal overgrowth, or Silver-Russell syndrome, which is associated with intrauterine growth retardation. Optimal fetal growth is essential for perinatal survival and has long-term consequences extending into adulthood. Given the high incidence of intrauterine growth retardation and the high risk of metabolic and cardiovascular complications in later life, further clinical and basic research is needed to develop accurate early diagnosis of aberrant fetal growth and novel therapeutic strategies.     

Diurnal regulation of plant growth

Life occurs in an ever-changing environment. Some of the most striking and predictable changes are the daily rhythms of light and temperature. To cope with these rhythmic changes, plants use an endogenous circadian clock to adjust their growth and physiology to anticipate daily environmental changes. Most studies of circadian functions in plants have been performed under continuous conditions. However, in the natural environment, diurnal outputs result from complex interactions of endogenous circadian rhythms and external cues. Accumulated studies using the hypocotyl as a model for plant growth have shown that both light signalling and circadian clock mutants have growth defects, suggesting strong interactions between hypocotyl elongation, light signalling and the circadian clock. Here, we review evidence suggesting that light, plant hormones and the circadian clock all interact to control diurnal patterns of plant growth.     

Autonomous regulation of growth cone filopodia

The fan-shaped array of filopodia is the first site of contact of a neuronal growth cone with molecules encountered during neuronal pathfinding. Filopodia are highly dynamic structures, and the “action radius” of a growth cone is strongly determined by the length and number of its filopodia. Since interactions of filopodia with instructive cues in the vicinity of the growth cone can have effects on growth cone morphology within minutes, it has to be assumed that a large part of the signaling underlying such morphological changes resides locally within the growth cone proper. In this study, we tested the hypothesis that two important growth cone parameters namely, the length and number of its filopodiaare regulated autonomously in the growth cone. We previously demonstrated in identified neurons from the snail Helisoma trivolvis that filopodial length and number are regulated by intracellular calcium. Here, we investigated filopodial dynamics and their regulation by the second-messenger calcium in growth cones which were physically isolated from their parent neuron by neurite transection. Our results show that isolated growth cones have longer but fewer filopodia than growth cones attached to their parent cell. These isolated growth cones, however, are fully capable of undergoing calcium-induced cytoskeletal changes, suggesting that the machinery necessary to perform changes in filopodial length and number is fully intrinsic to the growth cone proper. © 1998 John Wiley & Sons, Inc. J Neurobiol 34: 179–192, 1998     

Endocrine regulation of the growth plate

Longitudinal bone growth occurs at the growth plate by endochondral ossification. Within the growth plate, chondrocyte proliferation, hypertrophy, and cartilage matrix secretion result in chondrogenesis. The newly formed cartilage is invaded by blood vessels and bone cells that remodel the newly formed cartilage into bone tissue. This process of longitudinal bone growth is governed by a complex network of endocrine signals, including growth hormone, insulin-like growth factor I, glucocorticoid, thyroid hormone, estrogen, androgen, vitamin D, and leptin. Many of these signals regulate growth plate function, both by acting locally on growth plate chondrocytes and also indirectly by modulating other endocrine signals in the network. Some of the local effects of hormones are mediated by changes in paracrine factors that control chondrocyte proliferation and differentiation. Many human skeletal growth disorders are caused by abnormalities in the endocrine regulation of the growth plate. This review provides an overview of the endocrine signals that regulate longitudinal bone growth, their interactions, and the mechanisms by which they affect growth plate chondrogenesis.     

Hormonal regulation of growth plate cartilage

Longitudinal bone growth occurs in the growth plate through a process called endochondral bone formation, a process where resting zone chondrocytes are recruited to start active proliferation and then undergo differentiation, followed by apoptosis and later mineralization. The balance between proliferation and differentiation is a crucial regulatory step controlled by various growth factors/hormones acting in both endocrine and paracrine/autocrine ways. From studies of individuals with aromatase deficiency and a boy with defective oestrogen receptor (ER)-alpha it has become clear that oestrogen action is indispensable for normal pubertal growth and growth plate fusion. Both oestrogen receptors, ER-alpha and ER-beta, are expressed in the growth plate in boys and girls throughout pubertal development. Any functional role of ER-beta has not yet been defined in the human growth plate. Increased understanding about the effects of oestrogen and the interactions between oestrogens and other endocrine factors within the growth plate is important for the development of new treatment strategies in different disorders affecting longitudinal bone growth. As new specific modulators of oestrogen receptors are developed, these could offer more specific ways to modulate longitudinal growth and growth plate fusion.     

Hyperthermia in cancer growth regulation

With present techniques, hyperthermia used alone can cause complete clinical regression in 10–15% of tumours but the duration of response is very short. The greatest advantage for hyperthermia at the present time appears to be in combination with radiation in the local control of cancer growth. Currently, large randomised phase III studies are in progress to determine whether the addition of local hyperthermia to radiation or chemotherapy yields significant advantage. Phase III studies of wholebody hyperthermia in combination with chemotherapy are planned for the future and will include tumours with a high growth fraction such as small cell lung cancer and high grade non Hodgkins lymphoma.     

Cooperative growth regulation in coral-dwelling fishes

Dominant individuals often grow faster than subordinates because they gain a greater share of important resources. However, dominants should also strategically adjust their growth rates, relative to the size of subordinates, if this improves their reproductive success. Here, we show that individuals in breeding pairs of the coral-dwelling fish Gobiodon histrio regulate their growth to reduce the size difference between partners. In pairs where one individual was larger than the other, the smaller individual increased its growth rate and the larger individual decreased its growth rate, compared to individuals in size-matched pairs. The reproductive success of breeding pairs is limited by the size of the smallest individual in the pair. Therefore, it appears that the larger individual trades-off its own growth against that of the smaller individual, thereby improving the reproductive success of both individuals in the pair. This demonstrates a remarkable ability of individuals to strategically adjust their body size to suit the local social environment, and reveals a novel mechanism for size-assortative mating.     

Interferon gamma-mediated growth regulation of epithelial cells

Interferon gamma (IFNgamma) is known to inhibit proliferation of certain transformed cell lines. Recently, we have demonstrated the transactivation of the epidermal growth factor receptor (EGFR) in response to IFNgamma (Burova et al., 2007) and provided direct evidence for the dependence of IFNgamma-induced EGFR transactivation upon EGFR expression level in epithelial cells (Gonchar et al., 2008). This study examines an antiproliferative effect of IFNgamma on human epithelial cells lines A431 and HeLa which express high levels of EGFR, as well as HEK293, which expresses low levels of EGFR. We characterized the IFNgamma-induced changes in these cells by studying cell growth, the cell cycle and induction of apoptosis. The response to IFNgamma differed in the tested cell lines: cell growth was inhibited in both A431 and HeLa cells, but not in HEK293 cells, as shown by cell counts and MTT. The cell cycle phases analyzed by flow cytometry were disturbed in A431 and HeLa cells in response to IFNgamma. In contrast, IFNgamma treatment did not alter distribution by cell cycle phases in HEK293. Our results indicate that IFNgamma exhibit an antiproliferative effect depending on the increased expression of EGFR in A431 and HeLa cells. Further, it was demonstrated that IFNgamma induced the caspase 3 activation in A431 cells, suggesting an involvement of active caspase 3 in IFNgamma-induced apoptosis.     

Tumor suppressor gene regulation of cell growth

The development of cancer involves a myriad of genetic changes that impact on multiple processes important for the orderly regulation of cell growth and differentiation. Genes whose protein products are disrupted during neoplastic transformation are termed “tumor suppressor genes” (TSGs). Many of these TSGs are associated with familial cancer predisposition syndromes, in which affected individuals have an increased risk of certain malignancies. Studies on the mechanism of action for known TSGs have revealed three intracellular loci of critical importance: environmental sensing and signal initiation, signal propagation and transduction, and cell cycle control. The neurofibromatosis 1 and neurofibromatosis 2 genes are discussed as illustrative examples of tumor suppressors that function at the levels of signal transduction and environmental sensing, respectively.