Increasing haemoglobin beta-chain syntheses in foetal development is associated with a declining gamma-to alpha-mRNA ratio.

Abstract

DURING human foetal development, the predominant haemoglobin in erythrocytes switches twice (Fig. 1). First, ɛ chains of embryonic haemoglobins in erythroblasts of yolk sac origin are replaced by γ chains of foetal haemoglobin and traces of β chains of adult haemoglobin. This switch occurs very early in foetal development, coincident with the appearance of a new type of peripheral erythrocyte of hepatic origin. Second, at about 32 weeks of gestation, predominantly γ-chain production gives way to increased β-chain synthesis within a constant cell type1. This double haemoglobin switch also occurs in other animals, including sheep2. Not only is very little known about the biological basis for the switch from γ- to β-chain production, but the basic changes in gene activity involved in the switching process are obscure. An understanding of the γ to β switch has clinical importance, for if one could block the switch and increase γ-chain production, sickle cell anaemia and β-thalassaemia could be treated effectively. We present here data concerning changes in globin gene activity, as assessed by globin mRNA levels, which are temporally related to the turning up of β-chain synthesis. These observations were originally made in erythroid cells of aborted human foetuses and were extended to cells from foetal sheep.