Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis AMice carrying null mutations of the genes encoding insulin-like growth factor-I (IGF-1) and type-1 IGF receptor (IGF1r). Cell 75: 59-72

Department of Genetics and Development, Columbia University, New York, New York 10032.
Cell (Impact Factor: 32.24). 11/1993; 75(1):59-72. DOI: 10.1016/S0092-8674(05)80084-4
Source: PubMed


Newborn mice homozygous for a targeted disruption of insulin-like growth factor gene (Igf-1) exhibit a growth deficiency similar in severity to that previously observed in viable Igf-2 null mutants (60% of normal birthweight). Depending on genetic background, some of the Igf-1(-/-) dwarfs die shortly after birth, while others survive and reach adulthood. In contrast, null mutants for the Igf1r gene die invariably at birth of respiratory failure and exhibit a more severe growth deficiency (45% normal size). In addition to generalized organ hypoplasia in Igf1r(-/-) embryos, including the muscles, and developmental delays in ossification, deviations from normalcy were observed in the central nervous system and epidermis. Igf-1(-/-)/Igf1r(-/-) double mutants did not differ in phenotype from Igf1r(-/-) single mutants, while in Igf-2(-)/Igf1r(-/-) and Igf-1(-/-)/Igf-2(-) double mutants, which are phenotypically identical, the dwarfism was further exacerbated (30% normal size). The roles of the IGFs in mouse embryonic development, as revealed from the phenotypic differences between these mutants, are discussed.

  • Source
    • "Via their respective receptors, these stimuli converge on downstream pathways controlling the induction of adaptive gene programs and protein synthesis, and direct cellular metabolism and energy production. Well-characterized cascades and pathways regulating these homeostatic mechanisms comprise phosphoinositide 3 kinase (PI3K)/AKT, mTOR complex 1 (mTORC1), ERK1/2 and AMP-activated protein kinase (AMPK) (Baker et al., 1993; Liu et al., 1993; McMullen et al., 2003; Seth et al., 2009; Bostrom et al., 2010; Zhang et al., 2010). Translating stretch-stimuli to downstream signaling, the mechanosensing apparatus is controlled by transient receptor potential (TRP) channels, integrins and various z-disc associated proteins such as muscle LIM protein (MLP), actinin-associated LIM protein (ALP) and Nebulette (NEB) as well as the sarcomere-spanning protein titin (Linke, 2008; Seth et al., 2009; Frank and Frey, 2011; Luedde et al., 2011; Hamdani et al., 2013; Maillet et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cardiac remodeling describes the heart's multimodal response to a myriad of external or intrinsic stimuli and stressors most of which are probably only incompletely elucidated to date. Over many years the signaling molecules involved in these remodeling processes have been dichotomized according to a classic antagonistic view of black and white, i.e., attributed either a solely maladaptive or entirely beneficial character. By dissecting controversies, recent developments and shifts in perspective surrounding the three major cardiac signaling molecules calcineurin (Cn), protein kinase A (PKA) and calcium/calmodulin-dependent kinase II (CaMKII), this review challenges this dualistic view and advocates the nature and dignity of each of these key mediators of cardiac remodeling as a multilayered, highly context-sensitive and sophisticated continuum that can be markedly swayed and influenced by a multitude of environmental factors and crosstalk mechanisms. Furthermore this review delineates the importance and essential contributions of degradation and proteolysis to cardiac plasticity and homeostasis and finally aims to integrate the various aspects of protein synthesis and turnover into a comprehensive picture.
    Full-text · Article · Aug 2015 · Frontiers in Physiology
    • "In this sense, the mutual antagonism between the CNP and Fgf18 signaling pathways can be viewed as a sensing mechanism to ensure that a sufficient number of proliferating and prehypertrophic chondrocytes are present to initiate the hypertrophic chondrocyte differentiation program in that subset of these cells that lies distal to the source of PTHrP signals. IGF1 signaling controls the last phase of growth during chondrocyte hypertrophy Loss of IGF1 signaling is known to severely decrease long bone growth in both mice (Liu et al., 1993; Powell-Braxton et al., 1993) and human (Woods et al., 1996). In mice engineered to lack IGF1, chondrocyte numbers and proliferation are normal in the growth plates, but the size of the hypertophic chondrocytes is ∼30% smaller in the direction of elongation than in wild-type mice (Wang et al., 1999a). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Decades of work have identified the signaling pathways that regulate the differentiation of chondrocytes during bone formation, from their initial induction from mesenchymal progenitor cells to their terminal maturation into hypertrophic chondrocytes. Here, we review how multiple signaling molecules, mechanical signals and morphological cell features are integrated to activate a set of key transcription factors that determine and regulate the genetic program that induces chondrogenesis and chondrocyte differentiation. Moreover, we describe recent findings regarding the roles of several signaling pathways in modulating the proliferation and maturation of chondrocytes in the growth plate, which is the 'engine' of bone elongation. © 2015. Published by The Company of Biologists Ltd.
    No preview · Article · Mar 2015 · Development
  • Source
    • "Although fetal circulating IGF-II levels are higher throughout gestation, only free circulating IGF-I concentrations have consistently been shown to be reduced in FGR (Lassarre et al. 1991; Cianfarani et al. 1998). A 40 % decrease in fetal weight observed in IGF-I knockout mice with increased neonatal death provides a dramatic illustration of the critical role of IGF-I in normal fetal growth (Liu et al. 1993; Baker et al. 1993). IGF-I primarily exists in circulation bound to IGFBPs, and the endocrine responses of IGF-I are primarily mediated by binding to the IGF1 receptor (IGF1R). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Fetal growth restriction (FGR) increases the risk of perinatal complications and predisposes the infant to developing metabolic, cardiovascular, and neurological diseases in childhood and adulthood. The pathophysiology underlying FGR remains poorly understood and there is no specific treatment available. Biomarkers for early detection are also lacking. The insulin-like growth factor (IGF) system is an important regulator of fetal growth. IGF-I is the primary regulator of fetal growth, and fetal circulating levels of IGF-I are decreased in FGR. IGF-I activity is influenced by a family of IGF binding proteins (IGFBPs), which bind to IGF-I and decrease its bioavailability. During fetal development the predominant IGF-I binding protein in fetal circulation is IGFBP-1, which is primarily secreted by the fetal liver. IGFBP-1 binds IGF-I and thereby inhibits its bioactivity. Fetal circulating levels of IGF-I are decreased and concentrations of IGFBP-1 are increased in FGR. Phosphorylation of human IGFBP-1 at specific sites markedly increases its binding affinity for IGF-I, further limiting IGF-I bioactivity. Recent experimental evidence suggests that IGFBP-1 phosphorylation is markedly increased in the circulation of FGR fetuses suggesting an important role of IGFBP-1 phosphorylation in the regulation of fetal growth. Understanding of the significance of site-specific IGFBP-1 phosphorylation and how it is regulated to contribute to fetal growth will be an important step in designing strategies for preventing, managing, and/or treating FGR. Furthermore, IGFBP-1 hyperphosphorylation at unique sites may serve as a valuable biomarker for FGR.
    Full-text · Article · Feb 2015 · Journal of Cell Communication and Signaling
Show more