Nerve Growth Factor and Related Substances: a Brief History and an Introduction to the International NGF Meeting Series
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International Journal of Molecular Sciences Editorial Nerve Growth Factor and Related Substances: A Brief History and an Introduction to the International NGF Meeting Series Ralph A. Bradshaw 1,2, William Mobley 3 and Robert A. Rush 4,* 1 Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA; [email protected] 2 Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA 3 Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093, USA; [email protected] 4 Department of Human Physiology, Flinders University, Adelaide, SA 5001, Australia * Correspondence: robert.rush@flinders.edu.au; Tel.: +61-4-1419-0126 Academic Editors: Margaret Fahnestock and Keri Martinowich Received: 12 April 2017; Accepted: 10 May 2017; Published: 26 May 2017 Abstract: Nerve growth factor (NGF) is a protein whose importance to research and its elucidation of fundamental mechanisms in cell and neurobiology far outstrips its basic physiological roles. It was the first of a broad class of cell regulators, largely acting through autocrine and paracrine interactions which will be described herein. It was of similar significance in establishing the identity and unique roles of neurotrophic factors in the development and maintenance of the peripheral and central nervous systems. Finally, it contributed to many advances in the elaboration of cell surface receptor mechanisms and intracellular cell signaling. As such, it can be considered to be a “molecular Rosetta Stone”. In this brief review, the highlights of these various studies are summarized, particularly as illustrated by their coverage in the 13 NGF international meetings that have been held since 1986. Keywords: growth factors; neurotrophins; cell signaling; receptors; central nervous system; development 1. Pre-Meeting History The discovery of nerve growth factor (NGF) is appropriately attributed to Rita Levi-Montalcini in the early 1950s, while she was working as a visiting scientist in the laboratory of Viktor Hamburger in St. Louis, Missouri. (Many fine reviews have been published over the past decades and represent a compendium of the history of NGF research, covering essentially all aspects of the chemistry and biology of it and its many related substances. References [1–9] are a sampling of such material and a good starting point for readers interested to read more details). However, it can be argued that the first experimental observations of its activity were made by Elmer Bueker with transplanted tumors (mouse sarcomas 37 and 180) a few years earlier [10]. Levi-Montalcini recognized that the hypertrophic effects exerted on the host (mouse) sympathetic neurons by the tumors was likely due to a soluble substance, in keeping with her previous proposals developed in Italy during the Second World War. Indeed, many years later when asked by one of us (Bill Mobley) when she knew she had discovered something uniquely different, Rita replied it was when she saw “axons invading blood vessels” for the first time. For her, this phenomenon marked a radical departure from the norm and pointed to a powerful new activity present. Its identification was the first step in revealing a new and very different story. To purify the activity, Rita devised an assay for the material, which she ultimately named NGF, (“Nerve growth factor” was actually not the first name given to it; rather it was originally termed nerve growth-promoting activity. However, this name was of short duration and was quickly supplanted by the growth factor designation. Stanley Cohen solidified this terminology when Int. J. Mol. Sci. 2017, 18, 1143; doi:10.3390/ijms18061143 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2017, 18, 1143 2 of 11 Int. J. Mol. Sci. 2017, 18, 1143 2 of 11 name was of short duration and was quickly supplanted by the growth factor designation. Stanley Cohen solidified this terminology when he named epidermal growth factor). This assay, developed hein Rio named de Janeiro epidermal in the growth laboratory factor). of This a colleagu assay,e, developed Hertha Meyer, in Rio ultimately de Janeiro inused the explanted laboratory chick of a colleague,dorsal root Hertha ganglia Meyer, in an ultimatelyinverted semi-solid used explanted plasma chick clot. dorsal Tumor-induced root ganglia fiber in an growth inverted radiated semi-solid out plasmato produce clot. a Tumor-induced halo-like effect fiberand growththe original radiated phot outographs to produce are an aiconic halo-like part effect of biological and the originalart (See photographsFigure 1) [1]. areWhile an iconicLevi-Montalcini part of biological went on art to (Seedefine Figure the 1biological)[ 1]. While properti Levi-Montalcinies of this material, went on she to defineworked the in biologicalcollaboration properties with Stanley of this Cohen material, to sheattempt worked the infirst collaboration isolation of withNGF Stanleyfrom the Cohen tumors to attempt[11]. Serendipitously, the first isolation they of NGF identified from the tumorssnake [11venoms,]. Serendipitously, then ultimately they identified adult snakemale venoms,mouse thensubmandibular ultimately adultglands male as considerably mouse submandibular richer sources glands of asNGF considerably [12,13]. The richer latter sources provided of NGF sufficiently [12,13]. Thepurified latter material provided to sufficientlygenerate anti-sera. purified Cohen material also to showed generate that anti-sera. the submandibular Cohen also showedtissue contained that the submandibulara second abundant tissue substance, contained epidermal a second abundant growth substance,factor (EGF), epidermal which he growth eventually factor (EGF),isolated which and hecharacterized eventually [14]. isolated EGF and turned characterized out to be at [14 least]. EGF as important turned out as to NGF be at to least cell asbiology.The important anti-mouse as NGF to cellNGF biology.The proved effective anti-mouse in eliminating NGF proved the effective developm in eliminatingent of the sympathetic the development nervous of thesystem sympathetic (giving nervousrise to the system technique (giving riseof immunosympathectomy) to the technique of immunosympathectomy),, providing concrete providing proof of concrete the biological proof of thesignificance biological of significance NGF [15] ofthree NGF decades [15] three before decades advances before in advances molecular in molecular biology allowed biology allowedfor similar for similarconclusions conclusions by using by knockout using knockout animals animals [16]. [16]. Figure 1. Nerve growth factor (NGF) “Halo” effect on cultured peripheral ganglia. Figure 1. Nerve growth factor (NGF) “Halo” effect on cultured peripheral ganglia. With the identification of the submandibular gland source of NGF, two groups isolated the activityWith to theapparent identification homogeneity, of the submandibular but surprisingly gland with source quite of different NGF, two results. groups Eric isolated Shooter’s the activity group toat apparentStanford homogeneity,and Silvio Varon’s but surprisingly group at withUniversity quite different of California, results. San Eric Diego, Shooter’s working group atin Stanfordconcert, anddescribed Silvio Varon’sa high groupmolecular at University weight complex, of California, denoted San Diego,7S NGF, working containing in concert, three described types of a highpolypeptides molecular (termed weight α complex,, β and γ denoted) [17,18], 7Swhile NGF, Piero containing Angeletti’s three lab types in Rome of polypeptides reported a (termedsmaller αentity,, β and whichγ)[17 they,18], called while 2.5S Piero NGF Angeletti’s [19] (the lab S desi in Romegnations reported referring a smaller to their entity, relative which sedimentation they called 2.5Scoefficients). NGF [19 ]Only (the Sone designations of the subunits referring of th toe their7S complex relative had sedimentation neurite-stimulating coefficients). activity Only (β oneNGF), of theand subunits its similar of size the 7Sto 2.5S complex NGF hadsuggested neurite-stimulating that this was activitythe principal (βNGF), biological and its entity, similar (the size α to and 2.5S γ NGFsubunits suggested were ultimately that this wasshown the to principal be members biological of a large entity, group (the ofα mouseand γ subunitsglandular were kallikreins ultimately that shownare essentially to be members unique to of th aat large tissue group and ofspecies. mouse The glandular γ subunit kallikreins has proteolytic that are activity essentially and causes unique the to thatexcision tissue of anda dipeptide species. Thefromγ thesubunit C-terminus has proteolytic of the β activitysubunit andof mouse causes NGF the excision but with of no a dipeptide apparent fromphysiological the C-terminus relevance). of the Inβ 1971,subunit Ruth of Angeletti mouse NGF and but Ralph with Bradshaw no apparent determined physiological that mouse relevance). 2.5S InNGF 1971, was Ruth a non-covalently Angeletti and Ralphassociated Bradshaw homodimer determined [20] thatand mousereported 2.5S the NGF monomeric was a non-covalently amino acid associatedsequence as homodimer a protein of [20 118] and amino reported acids the with monomeric three intrachain amino acid disulfide sequence bonds as a [21]. protein In the of 118following amino acidsyear, withBill Frazier three intrachain analyzed both disulfide the primary bonds [21 stru]. Incture the followingand the known year, Billfunctional Frazier properties analyzed both of NGF the primaryand concluded