The phenotype of neurosecretory cells is characterized by clear vesicles and dense granules, both discharged by regulated exocytosis. However, these organelles are lacking completely in a few neurosecretion-incompetent clones of the pheochromocytoma PC12 line, in which other specific features are maintained (incompetent clones). In view of the heterogeneity of PC12 cells, a differential characterization of the incompetent phenotype based on the comparison of a single incompetent and a single wild-type clone would have been inconclusive. Therefore, we have compared two pairs of PC12 clones, studying in parallel the transcript levels of 4,200 genes and 19,000 express sequence tags (ESTs) by high density oligonucleotide arrays. After accurate data processing for quality control and filtration, a total of 755 transcripts, corresponding to 448 genes and 307 ESTs, was found consistently changed, with 46% up-regulated and 54% down-regulated in incompetent versus wild-type clones. Many but not all neurosecretion genes were profoundly down-regulated in incompetent cells. Expression of endocytosis genes was normal, whereas that of many nuclear and transcription factors, including some previously shown to play key roles in neurogenesis, was profoundly changed. Additional differences appeared in genes involved in signaling and metabolism. Taken together these results demonstrate for the first time that expression of neurosecretory vesicles and granules is part of a complex gene expression program that includes many other features that so far have not been recognized.Expression of two classes of secretory organelles, small translucent vesicles (clear vesicles) and dense content granules of larger size (DGs), 1 is the typical trait of neurosecretory cells.These organelles resemble in many respects the synaptic organelles of neurons and share with them the property to be discharged by regulated exocytosis. Clear vesicles, DGs, and their synaptic counterparts have attracted uninterrupted attention for many years and are, therefore, among the best known organelles not only in terms of composition and structure but also in relation to the processes they are involved in such as assembly, loading of neurotransmitters, exocytotic membrane fusion, and recycling (for reviews see Refs. 1 and 2).In contrast, only a few studies have been devoted to the mechanisms whereby cells acquire neurosecretion competence. Knowledge in the latter field is therefore limited (see Refs.
3-5).In previous studies, expression of other specific functions was identified as an independent process in the course of cell differentiation. In both neuronal and neurosecretory systems, however, neurosecretion seems to appear concomitantly with the expression of other traits such as neurite outgrowth and synaptogenesis (3,4,6,7). This suggested neurosecretion competence is not independent but coordinate with other functions in a wider differentiation program. This interpretation appears open to question, because the isolation, from the well-known neurosecretion comp...