Arch Dis Child: first published as 10.1136/adc.64.1_Spec_No.53 on 1 January 1989. Downloaded from Archives of Disease in Childhood, 1989, 64, 53-57 Current topic Fetal growth signals R D G MILNER AND D J HILL Department of Paediatrics, Children's Hospital, Sheffield Human fetal growth is not uniform. Tissue patterns growth factor fi like peptide is found in the vegetal and organ primordia are established during embryo- pole ectoderm of the early Xenopus embryo and is genesis, then from the end of the first trimester and transcribed by a maternally derived gene designated throughout the second the fetus undergoes massive Vgl. An ectodermal cell line, XTC, from the meta- hyperplasia. In the third trimester further organ morphosing tadpole releases a transforming growth modelling and functional maturation occur in pre- factor I8 like peptide in vitro.5 In the 11-18 day fetal paration for extrauterine life. Each aspect ofdevelop- mouse transforming growth factor 3 can be detected ment requires orchestrated intercellular signalling at in bone and connective tissue, particularly that two levels. The release of peptide growth factors derived from neural crest such as palate, larynx, and the modulation of an extracellular matrix are facial mesenchyme, and teeth.6 Staining was most paracrine actions that occur within cell populations intense at sites of tissue morphogenesis affecting and between adjacent germ layers. In contrast, mesodermal and epithelial interaction such as hair endocrine hormones may stimulate growth non- follicles, teeth, and secondary palate. copyright. specifically or promote specific maturational events. Recently both fibroblast growth factor and trans- The interactions between paracrinology, endocrino- forming growth factor i have been shown to exert logy, and environmental constraints to growth remarkable effects on embryonal morphology. during normal and abnormal fetal development Induction of mesoderm in the amphibian embryo have been reviewed in detail recently.1 2 In this depends on morphogens from the ectoderm of the commentary emphasis has been placed on new vegetal pole diffusing to cause mesodermal develop- concepts of embryonic and fetal growth control. ment in the ectoderm of the animal pole. Fibroblast growth factor induces mesoderm in Xenopus animal Paracrinology pole ectoderm in vitro, the structures developing being mainly mesenchyme, mesothelium, and blood http://adc.bmj.com/ Peptide growth factors act on cell cultures in vitro to cells enveloped in ectoderm.7 Transforming growth stimulate differentiation, functional activity, and factor PI also induces mesoderm in Xenopus ecto- chemotaxis as well as causing cell proliferation.3 derm, especially muscle, which was identified by the Though this has led to speculation that peptide presence of a actin mRNA.s The most potent growth factors are fundamental to prenatal develop- natural source of mesoderm inducing activity is ment, the technology and purified peptides to test conditioned medium from Xenopus XTC cell the relevant hypotheses in vivo have only recently cultures, and this can be blocked by transforming become available. growth factor 13 antiserum. Fibroblast growth factor on October 1, 2021 by guest. Protected promotes mitosis, cell migration, invasion, and FIBROBLAST GROWTH FACTOR AND TRANSFORMING production of plasminogen activator by vascular GROWTH FACTOR fi endothelial cells, which are all necessary features of It is now clear that at least two peptide growth angiogenesis in vivo.8 It also induces the differentia- factors, fibroblast growth factor and transforming tion of chondrocytes, preadipocytes, astrocytes, and growth factor 3 are present early in embryogenesis oligodendrocytes. Not all actions offibroblast growth and are potentially concerned with germ layer factor on tissue differentiation are augmentative, as separation. Fibroblast growth factor has been identi- it attenuates the differentiation and fusion of fetal fied in chick embryo from day 11 of incubation and myoblasts and decreases concentrations of muscle messenger ribonucleic acid (mRNA) for fibroblast specific enzymes such as myokinase. Of particular growth factor has been located in the Xenopus relevance to embryogenesis is the avid association of blastula.4 Messenger RNA encoding a transforming fibroblast growth factor with heparin sulphate, a 53 Arch Dis Child: first published as 10.1136/adc.64.1_Spec_No.53 on 1 January 1989. Downloaded from 54 Milner and Hill glycosaminoglycan produced in large amounts by and human development insulin like growth factors vascular and corneal endothelium and a structural are strongly associated with populations of differen- component of their extracellular matrix. tiated functional cells, suggesting that their role is to Fibroblast growth factor may act in a novel way support this phenotype. Both insulin like growth because its gene does not encode the conventional factors are not only mitogenic but also induce peptide sequence that is necessary for vesicle differentiation.2 Insulin like growth factor I induces associated exocytosis.8 The peptide may leave the the fusion of inyoblasts and the appearance of cell together with matrix molecules, and either react muscle specific enzymes in postmitotic contractile immediately with fibroblast growth factor receptors myotubes; and is 100 times more potent than insulin as an autocrine stimulus, or remain stored within the like growth factor II in this respect. Insulin like matrix. Since organogenesis entails cells interacting growth factor I augments the action of follicle with newly formed matrix to promote stem cell stimulating hormone duringdifferentiation ofovarian growth and stabilise phenotype, it is possible that granulosa cells, leading to an increase in luteinising fibroblast growth factor might influence differentia- hormone receptors and sex steroid accumulation. tion from a matrix store. Whereas insulin like growth factor I promotes the differentiation of fetal brain astrocytes into oligo- INSULIN LIKE GROWTH FACTORS dendrocytes, insulin like growth factor II synergises There seems to be no report of insulin like growth with nerve growth factor to promote neurite out- factor being present in embryos before separation of growth from sensory and sympathetic ganglia. Both the germ layers. Studies with embryonal mouse insulin like growth factor I and II increase extra- carcinoma cell lines suggest that insulin like growth cellular matrix synthesis by connective tissues, factor II occurs only after differentiation of the particularly chondrocytes. pluripotential ectodermal cells by exposure to Plasma insulin like growth factor I and II in the retinoic acid to yield cells with mesodermal or human fetus rise gradually until full term, when like endodermal phenotypes. Insulin like growth factor insulin like growth factor I, but not insulin copyright. and epidermal growth factor may have a fundamen- growth factor II correlates with birth weight. If we tally different role from transforming growth factor accept that the main action of insulin like growth I1 and fibroblast growth factor. They are expressed factors is a local one, the biological interpretation of during and after the condensation of tissues and may circulating concentrations is difficult. Nevertheless influence expansion and differentiation of stem cell there is a sharp rise in plasma insulin like growth populations. factor II in the fetal rat, lamb, and guinea pig that is In the human fetus in the early second trimester, coincident with the onset of gluconeogenesis. insulin like growth factors have been localised by immunohistochemistry to epithelia within the gut, EPIDERMAL GROWTH FACTOR AND TRANSFORMING kidney, and lung, and to hepatocytes, fetal zone GROWTH FACTOR a adrenal cells, skeletal, and cardiac muscle fibres, Epidermal growth factor is also associated with cell http://adc.bmj.com/ haemopoietic cells, and dermis.9 This distribution differentiation and maturation during embryo- may be partly due to a complex of insulin like genesis. In the mouse embryo the first differentiated growth factor with specific binding protein attaching cell type, primary trophoectoderm, possesses epi- avidly to certain cell membranes. The binding dermal growth factor receptors that may be activated protein has been shown to potentiate the biological by either epidermal growth factor or its analogue actions of insulin like growth factors in vitro.10 The transforming growth factor a. Although transforming like factor growth factor a concentration is highest in the tissue distribution of insulin growth on October 1, 2021 by guest. Protected binding protein in the human fetus mirrors that of mouse embryo at day 7, transforming growth factor insulin like growth factor itself suggesting that the a mRNA cannot be detected at this time but is two coexist as a complex in or on certain cells.'1 This abundant in the maternal decidua, especially may reflect sequestration of insulin like growth adjacent to the embryo.13 Decidual expression factor, as in situ hybridisation studies show most began after implantation, peaked at day 8, then insulin like growth factor mRNA to be in fibrous slowly declined with decidual reabsorption. Trans- mesenchyme adjacent to the cell types positive for forming growth factor a may therefore be available insulin like growth factor. 12 to the embryo from a maternal source during Most insulin like growth factor mRNA in rat or gastrulation and neurulation. By early in the second human fetuses encodes insulin like