Pre-pro- precursors of the neurotrophins NGF, BDNF, NT-3, NT-4/5 are synthesized in various cell types by endoplasmic reticulum (ER) attached ribosomes, leading to sequestration of the newly formed polypeptide chain into the ER. The mouse NGF gene gives rise to two major transcripts that contain NGF (12.5 kDa) at the C-terminus and differ by alternative splicing of an N-terminal exon, so that the large precursor (34 kDa) has 67 amino acids upstream of an internal signal peptide and the smaller precursor (27 kDa) has this signal peptide at its N-terminus. The transcript for the large precursor predominates in the submaxillary gland, whereas the transcript for the smaller precursor predominates in virtually all other tissues.
The signal peptide is cleaved off immediately after sequestration into the ER. Therefore, expression of either NGF transcript gives rise to an apparently identical intracellular glycosylated precursor formed by cleavage of the primary gene product after the signal peptide.