Differential RNA splicing predicts two distinct nerve growth factor precursors

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Abstract
Nerve growth factor (NGF) has a crucial role in the development of sensory and sympathetic neurones1–6. However, although it can affect other neural cell types under certain experimental conditions7, no biological role has been convincingly demonstrated elsewhere in the nervous system. The 5′ end of the mouse NGF gene contains several relatively short exons8. The NGF messenger RNA contains two in-frame initiator methionine codons; the second precedes the signal peptide sequence. Studies of the translation of other eukaryotic mRNAs indicate that the first AUG is preferred, suggesting that the signal for secretion might be ambiguous. We have analysed the NGF mRNA species from various cell types, some of which (clonal myoblast and fibroblast cell lines) are known to secrete NGF9,10, to search for different NGF transcripts. One pathway of RNA splicing generates the transcript already described from a submaxillary gland complementary DNA clone11. We demonstrate here that there is another splicing pathway, leading to a shorter transcript that lacks the second exon. This short transcript is the major form in most other mouse tissues and in the tissues of several other species, but both transcripts are usually present. In the short transcript, the initiator methionine is immediately upstream from a signal peptide-like sequence whereas in the long transcript the first methionine is 62 amino acids upstream from the signal peptide-like sequences. This may result in a different cellular localization of the NGF or alter the biological activity of the NGF precursor.