CONTRASTING ROLES FOR C-MYC AND L-MYC IN THE REGULATION OF CELLULAR GROWTH AND DIFFERENTIATION IN-VIVO

Although myc family genes are differentially expressed during developm ent, their expression frequently overlaps, suggesting that they may se rve both distinct and common biological functions. In addition, altera tions in their expression occur at major developmental transitions in many cell lineages, For example, during mouse lens maturation, the gro wth arrest and differentiation of epithelial cells into lens fiber cel ls is associated with a decrease in L- and c-myc expression and a reci procal rise in N-myc levels. To determine whether the down-regulation of L- and c-myc are required for mitotic arrest and/or completion of d ifferentiation and whether these genes have distinct or similar activi ties in the same cell type, we have studied the consequences of forced L- and c-myc expression in the lens fiber cell compartment using the alpha A-crystallin promoter in transgenic mice (alpha A/L-myc and alph a A/c-myc mice). With respect to morphological and molecular different iation, alpha A/L-myc lenses were characterized by a severely disorgan ized lens fiber cell compartment and a significant decrease in the exp ression of a late-stage differentiation marker (MIP26); in contrast, d ifferentiation appeared to be unaffected in alpha A/c-myc mice. Furthe rmore, an analysis of proliferation indicated that while alpha A/L-myc fiber cells withdrew properly from the cell cycle, inappropriate cell cycle progression occurred in the lens fiber cell compartment of alph a A/c-myc mice. These observations indicate that continued late-stage expression of L-myc affected differentiation processes directly, rathe r than indirectly through deregulated growth control, whereas constitu tive c-myc expression inhibited proliferative arrest, but did not appe ar to disturb differentiation. As a direct corollary, our data indicat e that L-Myc and c-Myc are involved in distinct physiological processe s in the same cell type.