The myc family of cellular oncogenes contains three known members. The N-myc and c-myc genes have 5'-noncoding exons, strikingly homologous coding regions, and display similar oncogenic potential in an in vitro transformation assay. The L-myc gene is less well characterized, but shows homology to N-myc and c-myc (ref. 6; also see below). c-myc is expressed in most dividing cells, and deregulated expression of this gene has been implicated in the development of many classes of tumours. In contrast, expression of N-myc has been found only in a restricted set of tumours, most of which show neural characteristics; these include human neuroblastoma, retinoblastoma and small cell lung carcinoma (SCLC). L-myc expression has so far been found only in SCLC. Activated N-myc and L-myc expression has been implicated in oncogenesis; for example, although N-myc expression has been found in all neuroblastomas tested, activated (greatly increased) N-myc expression, resulting from gene amplification, is correlated with progression of the tumour. We now report that high-level expression of N- and L-myc is very restricted with respect to tissue and stage in the developing mouse, while that of c-myc is more generalized. Furthermore, we demonstrate that N-myc is not simply a neuroectoderm-specific gene; both N- and L-myc seem to be involved in the early stages of multiple differentiation pathways. Our findings suggest that differential myc gene expression has a role in mammalian development and that the normal expression patterns of these genes generally predict the types of tumours in which they are expressed or activated.

N-myc, a cellular gene related to the c-myc proto-oncogene, was originally identified on the basis of its very frequent amplification and overexpression in a restricted set of tumours, most notably human neuroblastomas. That N-myc may have a causal role in the genesis of these tumours is suggested by the observation that in the rat embryo fibroblast co-transformation assay it has a transforming potential similar to that of c-myc. The apparent structural and functional homology of N-myc and c-myc suggests that they may be members of the same protooncogene family. However, despite these apparent similarities, expression of the two genes appears to be dramatically different with respect to tumour specificity, as well as tissue and developmental stage specificity. To further elucidate the common and unique aspects of N-myc and c-myc gene structure and function in normal and transformed cells, we have determined the organization of human N-myc and the nucleotide sequence of its messenger product, and we report here that N-myc and c-myc have a similar intron/exon structure and that their protein products share regions of significant homology.

In neuroblastoma lines in which the N-myc gene is present as a single copy, the expression of N-myc as messenger RNA is increased relative to that in nonneuroblastoma cell lines and tumors. The increase of expression in neuroblastomas with amplified N-myc genes is the result of (i) an increase in the absolute amount of expression of each N-myc gene and (ii) an increase in the copy number of the N-myc gene. A second gene--which is amplified in many of the same lines as N-myc--is expressed to about the same degree in most human cell lines and primary tumors regardless of origin (when normalized to gene copy number). Thus, a change in the regulation of N-myc expression in neuroblastomas and certain other tumors results in greatly increased expression of each N-myc gene copy.

Ardrenocorticotropic hormone (ACTH), beta-endorphin and the melanotropins (MSHs) are all derived from a single large precursor molecule, proopiomelanocortin (POMC) by individual processing through a series of co- and post-translational modifications. Although the primary site of synthesis is in the pituitary, POMC-derived peptides have been identified in various tissues, notably the brain (see refs 6, 7 for review). A major question concerning brain POMC is whether it is synthesized within the central nervous system (CNS) itself or whether it is taken up from plasma flowing in a retrograde fashion from the pituitary. POMC peptides have been detected immunohistochemically and biochemically in the medial basal hypothalamus, the amygdala and throughout the brain stem. POMC peptide-containing cell bodies have been identified only in two cell groups, however, principally in the periarcuate region of the hypothalamus and to a lesser extent in the nucleus of the tractus solitarius. These and other observations have suggested that POMC peptides are synthesized locally in the medial basal hypothalamus and reach other regions of the CNS by axonal transport. Civelli et al. identified POMC mRNAs in nucleic acid extracts of rat and bovine hypothalami by solution hybridization as well as Northern gel blot analysis, but because of the close proximity of the hypothalamus to the pituitary and the extremely low amounts of POMC mRNA being measured in the hypothalamus, the possibility of tissue contamination during dissection could not be ruled out. We report here the anatomical co-localization of POMC-related peptides and POMC-specific mRNAs to a single major cell group in the medial basal hypothalamus. The presence of POMC-specific mRNA in a POMC peptide-containing cell in the brain is strong support for POMC biosynthesis within brain tissue.