Cell Biology of Heme

Tissue-Specific Regulation of Iron Metabolism and Heme Synthesis: Distinct Control Mechanisms in Erythroid Cells

The chromosomal arrangement of human alpha-like globin genes: sequence homology and alpha-globin gene deletions.

Antibodies represent a complex eukaryotic system that has fascinated biologists for the past 75 years. The immune system has evolved novel and sophisticated strategies for dealing with extremely large amounts of information. These include strategies for information storage, information expression, and information evolution. Indeed, one of the driving forces in molecular immunology has been the attempt to formulate and analyze mechanisms responsible for the diversity of antibodies. Perhaps this consideration, more than any other, convinced many biologists that the immune system has evolved unique genetic strategies to protect the integrity of the vertebrate organism. We disagree with this viewpoint.

The Organization, Expression, and Evolution of Antibody Genes and Other Multigene Families

Symposium: New Perspectives on IronCell Biology of Heme

Embryonic and fetal hemoglobin in animals.

Evidence for erythroid and nonerythroid forms of δ-aminolevulinate synthetase.

Hemoglobin function in the horse: the role of 2,3-diphosphoglycerate in modifying the oxygen affinity of maternal and fetal blood.

The only reported work on sheep embryonic hemoglobin is that of Kleihauer and St0ffler.l These authors state that embryos with a crown-rump length of 8 to 10 mm. have blood composed of approximately 50% fetal hemoglobin and 50% a new hemoglobin type analogous in its electrophoretic mobility to the hemoglobin found at a similar stage of development in human embryos.', This new hemoglobin was termed embryonic hemoglobin. In the domestic sheep three distinct stages of hemoglobin production have been identified in the time span from the 20-day old embryo up to the adult animal (FIGURE 1 ) . This ontogeny, including the two transition events, is almost completely analogous to the ontogeny of hemoglobin occurring in man. In sheep, the transition of hemoglobin occurring at birth involves the disappearance of fetal hemoglobin (a,y,) and appearance of the adult hemoglobins over a time space of about two months starting at birth.., In sheep of hemoglobin B, Hb B type, the transition involves only fetal hemoglobin, Hb F, and adult Hb B; i.e., a disappearance of y chains and appearance of /3A chains. In sheep of Hb A (u,BZA) type the transition again is involved with disappearance of y chains, but the appearance of chains at birth is soon followed by the onset of Hb C ( a & C ) production, which peaks at 14-20 days making up only about 5-10% of circulating adult type hemoglobin at this time.' Hemoglobin C, termed an inducible hemoglobin because of its appearance during anemic states and when erythropoietin is administered,6 has no analogy in man, and its allelic site seems to be associated exclusively with the loci for Hb A. It is apparent that the Hb F to Hb A transition occurring in sheep occurs in a much shorter time space than that same transition in man, and that it is more closely associated with birth. In man the transition is begun several months prior to birth and is completed by six months after birth.3 The comparatively short period of time required for the Hb F to Hb A transition in sheep implies an event occurring concurrently in all hematopoietic tissue; an event that is initiated very close to birth. The other transition event occurring in sheep, which is the focal point of this paper, involves the switch from embryonic hemoglobin to fetal hemoglobin. Just as in man the transition involves the termination of embryonic hemoglobins and the onset of fetal hemoglobin. This transition in hemoglobin production

Ontogeny of hemoglobins in sheep.

Because of the impetus given by the finding of human hemoglobinopathies, numerous investigations of the animal hemoglobins have been instigated. In contrast to the human hemoglobins, marked heterogeneity of hemoglobins within many animal species has been reported.*-3 Certainly the occurrence of more than a single hemoglobin within a species is no longer considered unusual and certainly not pathological. Two classifications (TABLE 1) of animal hemoglobin heterogeneity can be described : nongenetic heterogeneity and generelated heterogeneity. Although this report will emphasize genetically related hemoglobin heterogeneity for which comparison to the human hemoglobinopathies will be made, the nongenetic causes of heterogeneity that may lead to misinterpretations in animal hemoglobin studies must be identified briefly.

Hyram Kitchen

Papers

Embryonic and fetal hemoglobin in animals.

Evidence for erythroid and nonerythroid forms of δ-aminolevulinate synthetase.

Hemoglobin function in the horse: the role of 2,3-diphosphoglycerate in modifying the oxygen affinity of maternal and fetal blood.

Ontogeny of hemoglobins in sheep.

Animal hemoglobin heterogeneity