PAX: developmental control genes in cell growth and differentiation.

Abstract

Embryonic development requires the generation of undifferentiated cells and their subsequent maturation into differentiated cells with a specific function. The molecular events that determine the identity of differentiated cells are evidently complex and, despite encouraging results, remain largely unknown. The development of individual undifferentiated cells into their mature differentiated phenotype requires the strict control of gene expression throughout their lifetime. In the developing embryo, gene expression must be regulated in both time and space to ensure that embryogenesis proceeds in a controlled manner and that the correct cell populations develop normally and in their correct position. The genes that direct these events are termed developmental control genes and, ultimately, they accomplish their task by influencing the activity of other genes or their gene products. In addition to their role in controlling embryonic development, these genes are prime candidates for involvement in oncogenesis because of their effects on cellular growth and differentiation. Developmental control genes encode a wide variety of proteins that act as nuclear transcription factors, e.g., HOX (1 , 2), engrailed (3, 4), and PAX (5, 6), secreted factors, e.g., Wnt (7), and membrane-bound receptors (8, 9). A key function of these genes is to influence the proliferation rate of their target cells so that cell migration and patterning events occur at the required time and in the required place. Also, other such genes must be able to inhibit further proliferation when it S not required. Here, we wish to describe how developmental regulatory genes may in part accomplish this task. In particular, we focus on the PAX family of genes and propose models to explain how some of these genes, via their interaction with other genes, influence the cell cycle. The PAX family of genes have been associated with three natural mouse developmental mutants and two corresponding human syndromes (Table 1 ; Ref. 6). In addition, their importance in the development of certain cell populations has been impressively documented by loss-of-function studies in the mouse (1 0) and especially in gain-of-function studies in Dmsophila, where PAX6 has been shown to be a master controller of eye development (1 1 , I 2). We concentrate primarily on PAX5 and its paralogues, PAX2 and PAX8, for three reasons: (a) they are the best characterized of all of the PAX genes; (b) their expression has been identified in a number of different human cancers; and (c) most importantly, their expression patterns in embryogenesis suggest that they play a central role in cell growth prior to terminal differentiation and are, therefore, likely candidates for oncogenesis.