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(1998) Prostaglandins promote and block adipogenesis through opposing effects on peroxisomal proliferator-activated receptor γ. J. Biol. Chem. 273, 1855–1858 79 Marques, B.G. et al. (1998) Association of fat cell size and paracrine growth factors in development of hyperplastic obesity. Am. J. Physiol. 275, R1898–R1908 80 Faust, I.M. et al. (1978) Diet-induced a dipocyte numbers increase in adult rats: a new model of obesity. Am. J. Physiol. 235, E279–E296 TRENDSin Endocrinology & Metabolism Vol.13 No.1 January/February 2002 http://tem.trends.com 1043-2760/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S1043-2760(01)00518-5 11 Review PDGF and the testis Stefania Mariani, Sabrina Basciani, Mario Arizzi, Giovanni Spera and Lucio Gnessi Testicular development and functional control involve a complex combination of cell proliferation, hypertrophy, migration, differentiation and apoptosis, which occur within strict temporal and anatomical constraints [1]. These highly coordinated processes, driven by the sequential activation of specific genes [2,3], require a precise temporal regulation of growth and differentiation of somatic and germ cell elements and imply several cell–cell interactions that are accomplished by locally produced growth and differentiation factors, hormones and cell adhesion molecules [4]. During the past decade, evidence has accumulated that shows that platelet-derived growth factor (PDGF) should be included as one of the locally produced growth factors that mediate testicular cell–cell interactions. This review focuses on the role of PDGF in the male gonad during prenatal and postnatal phases of development. Structure and general functions of PDGFs and PDGF receptors PDGF isoforms PDGFs are members of the PDGF-vascular endothelial growth factor (PDGF-VEGF) family of growth factors [5]. Their constituent polypeptide chains share a core motif of Cys residues with a characteristic spacing [6]. The three-dimensional structure of PDGFs is similar to that of VEGFs, but also bears some resemblance to the structures of glycoprotein hormones, of nerve growth factor and of the transforming growth factor β family of peptides, despite the fact that there is no amino acid sequence similarity among them [7]. All of these factors have dimeric configurations and show the characteristic Cys-knot motifs that are involved in the formation of inter- and intramolecular disulfide bonds [8]. For almost 20 years, only two PDGF polypeptides, PDGF-A and PDGF-B, were known. Recently, however, PDGF-C [9,10] and PDGF-D [11–13], two new PDGFs, were discovered. The biologically active PDGF molecules are either homodimers or heterodimers. The four homodimers, PDGF-AA, PDGF-BB, PDGF-CC and PDGF-DD, and the heterodimer, PDGF-AB, have all been shown to be endogenous cell products [14]. PDGF-C does not heterodimerize with PDGF-A or PDGF-B, probably because PDGF-C is rather distantly related to PDGF-A and PDGF-B in its core domain. By contrast, PDGF-C and PDGF-D are closely related structurally, but it remains to be established whether they can heterodimerize. PDGF-C and PDGF-D are as closely related to the VEGFs as they are to PDGF-A and PDGF-B, based on their primary sequence. However, they are characterized as novel PDGFs because of their PDGF receptor binding specificity. The A- and B-chains of PDGF are synthesized as precursor molecules that undergo proteolytic processing at the N-termini and, in the case of the B-chain, also intracellularly at the C-terminus [15]. Cells naturally producing both A- and B-chains contain all three PDGF isoforms, suggesting that the assembly of PDGF dimers could be a random process. PDGF bioavailability in vivo is also dependent on the association of the secreted growth factor with extracellular matrix molecules, which for PDGF-A and PDGF-B seems to be mediated by a C-terminal basic motif [16]. PDGF-C and PDGF-D possess an N-terminal domain (CUB domain; domain found in complement subcomponents C1r/C1s, urchin epidermal growth factor-like protein and bone Stefania Mariani Sabrina Basciani Mario Arizzi Giovanni Spera Lucio Gnessi* Dept Medical Physiopathology, Policlinico Umberto I, University of Rome ‘La Sapienza’, 00161 Rome, Italy. *e-mail: lucio.gnessi@uniroma1.it Testicular development is controlled by a complex hierarchy of gene regulatory proteins, growth factors, cell adhesion molecules, signaling molecules and hormones that interact, often acting w ithin short time w indow s, via reciprocal control relationships. The identification in the testis of platelet-derived grow th factor (PDGF), a key regulator of connective tissue cells in embryogenesis and pathogenesis, has focused attention on the role of this growth factor in testicular pathophysiology. This review summarizes recent advances in the study of the actions of PDGF in the male gonad, and attempts to incorporate complex in vitro and in vivo experimental data into a model that might clarify the role played by PDGF in the mammalian testis.