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An organism’s body size tells us a lot about how it makes a living, suggesting that body size is a key parameter in evolution. We outline three large-scale trends in body size evolution. Bergmann’s Rule is the tendency for warm-blooded species at high latitudes to be larger than their close relatives nearer the equator. The Island Rule is the trend for small species to become larger, and large species smaller, on islands. Cope’s Rule, which we discuss in much more detail, is the tendency for lineages to increase in size over evolutionary time. Trends are best studied by combining data on evolutionary relationships among species with fossil information on how characters have changed through time. After highlighting some methodological pitfalls that can trap unwary researchers, we summarise evidence that Cope’s Rule, while not being by any means universal, has operated in some very different animal groups — from microfauna (single-celled Foraminifera) to megafauna (dinosaurs) - and we discuss the possibility that natural selection and clade selection may pull body size in opposite directions. Despite size’s central importance, there is little evidence that body size differences among related groups affect their evolutionary success: careful comparisons rarely reveal any correlation between size and present-day diversity. We end by touching on human impacts, which are often more severe on larger species.

Sexual dimorphism in body size is a common feature of most animal species. While in many species, the female is the larger sex, in mammals, males are commonly larger, and greater male body mass and height are typical of primates. Growth of , however, is characterized by a number of unusual features, including rapid growth, a prolonged childhood phase, a pubertal spurt in stature, and a relative lack of sexual dimorphism, with adult male height averaging only 107% of that of females. The recent report of a female patient with a homozygous mutation of the gene for STAT5b, a critical component of the growth hormone (GH) signaling cascade responsible for insulin-like growth factor (IGF) gene transcription, has demonstrated that growth in both females and males is strongly pulsatile GH-STAT5b-IGF-dependent. This common dependence of both human females and males on the GH-STAT5b-IGF pathway may explain the relative lack of dimorphic growth characteristic of .

Size at birth is a heritable trait: estimates vary between 30% and 70%, but associations may be confounded by interactions with the maternal-uterine environment. Maternal smoking, length of gestation and parity could confound overall estimates of birth weight inheritance. However, the effects of maternal blood pressure, weight gain and glucose levels may be less easy to categorise, as they may reflect genetic factors acting in the mother. First pregnancies are associated with apparent “restraint” of fetal growth. Offspring birth weight in these pregnancies is lower and correlates closely with the mother’s own birth weight, possibly indicating a predominantly maternal inheritance. Candidate genes for maternal transmission of low birth weight include the mitochondrial DNA 16189 variant and exclusively maternally expressed genes such as . Offspring birth weight correlations with maternal blood pressure indicate that other maternal genes could influence size at birth in first pregnancies, where risk of pre-eclampsia is greatest. In subsequent pregnancies, gestational diabetes is linked to increased risk of macrosomia, and the impact of higher maternal glucose levels on larger offspring birth weight is demonstrated by a study of families with rare glucokinase gene mutations and in population studies of a common glucokinase gene promoter variant.

Larger birth weight shows a more autosomal mode of inheritance. Potential candidate genes reflect the importance of IGF-I, IGF-2, insulin and their respective receptors in regulating fetal growth, as shown by mouse knockout models and rare genetic variants in human subjects. Identification of common genetic variants associated with size at birth has been less successful. Birth weight association studies with polymorphisms in genes related to IGF-I, insulin and IGF-2 expression have yielded variable results. The common VNTR mini-satellite, which regulates INS and IGF2 expression, has been associated with size at birth and is confirmed by parental allele transmission, but has not been replicated in all populations. Animal data indicate the important role of imprinted genes in fetal growth, possibly reflecting the conflict between maternal and paternal influences on size at birth and fetal survival. Although evidence in contemporary human populations remains elusive, preliminary data indicate that such models remain important for future study.

Individuals develop from single cells through a genetically controlled program that regulates cell growth, cell proliferation and differentiation. The quantitative equilibrium between cell differentiation and proliferation is particularly important for tissue-specific growth and the shaping of higher organisms. Insulin-like growth factors (IGF) are key regulators of somatic growth, and growth hormone (GH), by controlling important aspects of IGF activity in many tissues in mammals, is able to coordinate this growth in a defined, spatio-temporal manner at the whole body level. Using homologous recombination, we generated mouse models with genetically determined IGF-1R insufficiency. We showed that partial inactivation of IGF-1R causes postnatal growth deficits that appear during the postnatal growth spurt and persist in the adult. We found that these growth deficits depend on the dosage of the IGF-1R gene. In our mutant mice, the postnatal growth of males relied more strongly on IGF-1R levels than the growth of females. Experiments using tissue-specific IGF-1R inactivation in the central nervous system provided evidence that IGF signaling in the brain may play a key role during the development of the somatotrope function in mammals.

Growth hormone (GH) activates a number of signaling pathways upon binding to its cognate receptor (GHR). Insights into downstream mechanisms of GH actions have been gained through the recent identification of a homozygous gene mutation in a young patient presenting with severe growth failure (height −7.5 SD) associated with normal GHR, elevated serum concentrations of GH, and markedly reduced serum IGF-I. At the cellular level, GH-induced genes that are STAT5b-dependent, such as IGF-I, were dysregulated, whereas regulation of other GH-responsive genes, such as SOCS2 and SOCS3, was unimpaired. The implication is that STAT5b has a unique and critical role in the growth-mediating actions of GH through regulating IGF-I expression. This finding is supported by the identification of a second case of mutation associated with GH insensitivity. The role(s) of the other signaling pathways has yet to be fully characterized. Clearly, the unmasking of the molecular bases for cases of GH insensitivity will greatly increase our understanding of both normal and aberrant human growth.

Growth hormone (GH) and IGF-I bind to specific membrane-bound receptors located in widely distributed target tissues. Although initial post-receptor signal transduction pathways differ - GH: associated tyrosine kinase (Jak) that activates signal transducers and activators of transcription (Stat) transcription factors; IGF-I: intrinsic tyrosine kinase that activates insulin receptor substrate (IRS) docking proteins, involved in several down stream effector pathways - many of the pathways are overlapping for GH and IGF-I, which makes it sometimes difficult to determine which hormone is responsible for the action being evaluated.

GH and IGF-I are best known for their stimulatory effects on the growth of bone and soft tissues. Most, but not all, of the known GH actions are mediated by circulating or endocrine IGF-I, produced essentially by the liver. However, many other tissues also synthesize GH and IGF-I locally, and thus each could also function as an autocrine/paracrine growth regulator. Recent in vivo studies using transgenic and classical or tissue-specific knockout models have helped shed light on how the two hormone/growth factors function. GH and IGF-I have independent as well as overlapping functions, and both are needed for maximal effect. However, increasing the circulating levels of IGF-I is frequently sufficient to induce a maximal response.

We examined bone development and remodeling in GH receptor (GHR) knockout (KO) and Stat5ab KO mice (kindly provided by J Kopchick and J Ihle). Markers of bone formation and resorption were reduced in GHR KO mice after two weeks of age. IGF-I treatment almost completely rescued all defects of bone growth and remodeling observed in GHR KO mice. Although bone length is slightly reduced in Stat5ab KO mice, the lack of any effect on trabecular bone remodeling or growth-plate width strongly suggests that the effects of GH in bone may not involve Stat5 activation.

The role of GH and IGF-I on reproductive functions was studied in female GHR KO mice. Litter size was markedly decreased in these animals due to a reduction in the rate of ovulation. IGF-I treatment was ineffective in rescuing this defect, suggesting that the effects of GH on follicular growth are independent of circulating IGF-I. In the same model, the actions of GH and IGF-I on muscle cell growth and differentiation were studied in vivo and in vitro. The absence of GH signaling resulted in a significant reduction in muscle mass without affecting the fiber number.

Almost all tissues except the liver express IGF-I transcripts in the absence of a functional GHR. Hepatic IGF-I production is dependent on GH, and this IGF-I, working together with GH, is primarily responsible for most of the growth signaling pathways, although this model may not be valid for all GH/IGF-I responsive tissues.

Numerous investigators have provided data supporting an essential role for IGF-I in growth of the brain. IGF-I contributes to multiple processes during brain development, including neural cell survival, proliferation, differentiation and maturation. The IGF type I receptor (IGF-IR) is present on all cell types in the brain, and IGF-I has known actions on neural stem and progenitor cells as well as neurons and glia. IGF-I is highly expressed throughout the brain during development, and its expression is retained in the meninges and in many cell types in the adult brain. While IGF-I has multiple actions on developing neural cells, very few studies have addressed the mechanisms or pathways by which IGF-I mediates these multiple effects. The goal of this chapter is to briefly review data on IGF-I in the developing brain and then to discuss more recent studies that focus on the mechanisms for its varied actions.

IGF-I deficiency may be caused by defects in growth hormone (GH) secretion or action. This chapter will focus on genetic mutations causing primary defects of IGF-I synthesis or disturbance of the GH-IGF-I axis resulting in GH insensitivity (GHI). Two patients with mutations of the IGF-I gene have been described. They have several features in common: intra-uterine growth retardation (IUGR), microcephaly, mental retardation, deafness, growth failure and variable insulin resistance. Mutations of the GH receptor (GHR) or downstream signaling pathway or of peptides essential for the formation of the ternary complex also cause IGF-I deficiency, resulting in some disturbance of linear growth. The phenotypic and endocrine features of these mutations causing GHI will also be discussed.

The growth hormone (GH)-insulin-like growth factor (IGF)-I axis is the dominant regulator of somatic growth in vertebrates. Growth deficits of varying severity follow experimental deletion of individual IGF axis components, with all but about 15% of the growth of an adult mouse explicable by the combined contributions of growth hormone and IGF-I stimulation. The type 1 IGF receptor mediates the growth-promoting actions of the IGFs and, when absent in mice, leads to severe fetal growth retardation and perinatal lethality. Thus, the IGF receptor is a critical element along the GH/IGF stimulatory pathway. Specific defects of IGF receptor function have not been unequivocally demonstrated to cause disease in humans until recently. We have described two patients with mutations in the Type 1 IGF receptor gene associated with fetal and postnatal growth retardation. One child was a compound heterozygote for missense mutations in the ligand binding domain. These mutations lowered the affinity of the IGF receptor for IGF-I and attenuated receptor signaling. The other child had a stop codon in exon 2 and showed a reduction in cell surface IGF receptor abundance. Though specific mutations within the receptor gene will be uncommon causes of fetal and prenatal growth deficits, deficits in IGF-I signaling, either at the receptor or post-receptor level, will likely be implicated in a much wider variety of growth disorders. The identification of additional patients with partial defects in IGF receptor function and their careful phenotyping will lead to a better understanding of the breadth and depth of IGF-I action in humans.

The growth hormone (GH)-insulin-like growth factor (IGF)-I axis is the dominant regulator of somatic growth in vertebrates. Growth deficits of varying severity follow experimental deletion of individual IGF axis components, with all but about 15% of the growth of an adult mouse explicable by the combined contributions of growth hormone and IGF-I stimulation. The type 1 IGF receptor mediates the growth-promoting actions of the IGFs and, when absent in mice, leads to severe fetal growth retardation and perinatal lethality. Thus, the IGF receptor is a critical element along the GH/IGF stimulatory pathway. Specific defects of IGF receptor function have not been unequivocally demonstrated to cause disease in humans until recently. We have described two patients with mutations in the Type 1 IGF receptor gene associated with fetal and postnatal growth retardation. One child was a compound heterozygote for missense mutations in the ligand binding domain. These mutations lowered the affinity of the IGF receptor for IGF-I and attenuated receptor signaling. The other child had a stop codon in exon 2 and showed a reduction in cell surface IGF receptor abundance. Though specific mutations within the receptor gene will be uncommon causes of fetal and prenatal growth deficits, deficits in IGF-I signaling, either at the receptor or post-receptor level, will likely be implicated in a much wider variety of growth disorders. The identification of additional patients with partial defects in IGF receptor function and their careful phenotyping will lead to a better understanding of the breadth and depth of IGF-I action in humans.