A NOVEL ISOFORM OF THE NEUROFIBROMATOSIS TYPE-1 MESSENGER-RNA AND A SWITCH OF ISOFORMS DURING MURINE CELL-DIFFERENTIATION AND PROLIFERATION

Four types of cDNAs encoding the GTPase-activating protein-related dom ain (GRD) of the mouse neurofibromatosis type-1 gene (NF1) have been c loned. One of these isoforms was a newly identified form termed type I V. Analysis of the genomic structure of the mouse NF1-GRD revealed two exons (23A and 23B) between exons 23 and 24, leading to the productio n of four types of NF1-GRD cDNAs by an alternative splicing mechanism. Amino-acid sequences encoded by NF1-GRD are highly conserved between human and mouse. Analysis of the expression of these transcripts in va rious tissues of adult mouse revealed that the type-I transcript is pr edominantly expressed in neural tissues such as brain and spinal cord. Other forms, termed types II, III and IV, are also expressed in vario us tissues. The type-I and type-II transcripts are expressed equivalen tly in undifferentiated P19 mouse teratocarcinoma cells, whereas type- I expression becomes predominant during neuronal differentiation by re tinoic acid treatment. Expression of type I is also shown to be correl ated with cessation of cell proliferation in P19 cells, but not in NIH 3T3 cells. These, together with other results, suggest that the four t ypes of NF1-GRD transcripts generated by alternative splicing have som e important biological roles in cell differentiation and proliferation .