[Identification of NPDC-1, gene involved in the control of proliferation and differentiation of neural and glial precursors].

Abstract

Most of the genes involved in the regulation of proliferation and differentiation of neural cells remain to be identified. With the aim of identifying such genes, the strategy we used was to search for cDNAs which both hybridized with helix-loop-helix degenerated probes and corresponded to RNAs expressed preferentially when neural precursor cells become growth-arrested and began to differentiate. This led to the isolation of NPDC-1 cDNA and then of the genomic sequence. We observed that NPDC-1 is specially expressed in the nervous system and that the transfection of neural precursors with NPDC-1 cDNA results in the inhibition of cell proliferation. Moreover, the stable introduction of NPDC-1 into transformed cells downregulates cell proliferation both by increasing the generation time and by suppressing transformed and tumorigenic properties. We verified that these biological effects were reversed by NPDC-1 anti-sense oligonucleotides. Then we have examined the expression of NPDC-1 mRNA along mouse development and the interactions of the NPDC-1 protein with cell cycle regulatory proteins. The results showed that NPDC-1 mRNA begins to be expressed in a variety of neural structures, when the precursors enter their terminal differentiation. In addition, we have observed that NPDC-1 protein interacts with the transcription factor E2F-1. As a whole, the present results show that NPDC-1 down-regulates the proliferation of neural precursors, is able to suppress oncogenic transformation, is involved in the terminal differentiation of neural cells and acts probably through interactions with E2F-1.