Neurotrophic actions of a novel molluscan epidermal growth factor

The mammalian epidermal growth factor (EGF) is expressed in the developing and adult CNS, and it has been implicated in the control of cell proliferat ion, differentiation, and neurotrophic events. Despite extensive evolutiona ry conservation of the EGF motif in a range of different types of proteins, secreted EGF homologs with neurotrophic actions have not been reported in invertebrates. In this study, we present a novel member of the family of EG F-like growth factors, an EGF homolog from the mollusc Lymnaea stagnalis (L -EGF), and we demonstrate that this protein has neurotrophic activity. Puri fied L-EGF is a 43-residue peptide and retains the typical structural chara cteristics of the EGF motif. The L-EGF cDNA reveals a unique precursor orga nization. In contrast to the multidomain mammalian EGFs, it consists of onl y two domains, a signal peptide and a single EGF motif. Conspicuously, the L-EGF precursor lacks a transmembrane domain, setting it apart from all oth er members of the EGF-family. L-EGF mRNA is expressed throughout embryonic development, in the juvenile CNS, but not in the normal adult CNS. However, expression in the adult CNS is upregulated after injury, suggesting a role of L-EGF in repair functions. This notion is supported by the observation that L-EGF evokes neurite outgrowth in specific adult Lymnaea neurons in vi tro, which could be inhibited by an EGF receptor tyrosine kinase inhibitor. In conclusion, our findings further substantiate the notion that the EGF f amily has an early phylogenetic origin, and our data support a neurotrophic role for L-EGF during development and injury repair.