Molecular mechanisms in erythroid differentiation.

The most striking molecular event during erythroid differentiation is the accumulation of haemoglobin but this is only one of many overt changes which occur in the maturing erythroid cell. Other proteins accumulate progressively, notably carbonic anhydrase and catalase while yet others, particularly the enzymes of haem synthesis, such as aminolaevulinic acid synthetase, accumulate during early maturation and diminish later (Freshney, R. I. and Paul, J. 1972). Membrane changes also occur. These include the accumulation of spectrin on the inner surface of the membrane, of specific antigens on the outer surface and changes in lectin binding properties. Simultaneously, there is progressive reduction of transcription leading eventually to a complete cessation of RNA synthesis and, indeed, in most mammals, to the extrusion of the nucleus itself. These changes are orchestrated in the orderly manner that we associate with many differentiating systems and, for this reason, erythropoiesis has been regarded as a very good model for investigating normal diff erentiation in mammals and, hopefully, therefore, for providing information about the mechanisms which are disturbed in leukaemia. In any experimental situation, it is desirable that one should be able to initiate the process at will and to follow at least some components of it in detail. Erythroid tissues readily respond to increased demand and at least Part of this response is mediated through erythropoietin which is produced in the juxtaglomerular cells of the kidney in response to anoxia and promotes the maturation of erythroblasts. It has been possible to purify erythropoietin at least partially and to demonstrate its effects on cultured erythroid tissue in Part of the requirement can be met by using these techniques. Relatively recently, however, an alternative System of considerable power has emerged following the discovery that Friend erythroleukaemic cells of the mouse can be induced to synthesise large amounts of haemoglobin when treated with dimethylsulphoxide although normally they synthesise minimal amounts 1971). Experiments with both these systems will be discussed. In analysing the places in metabolic pathways where the accumulation of a protein can be controlled, the first principle to be appreciated is that accumulation occurs when the protein, Degradation synthesis exceeds degradation. This applies both to the final product, and also to intermediates in its synthesis such as messenger RNA. is unquestionably just as important as synthesis but here are more