The Role of SCL Isoforms in Embryonic Hematopoiesis

Abstract

Three waves of hematopoiesis occur in the mouse embryo. The primitive hematopoiesis appears as blood islands in the extra embryonic yolk sac at E7.5. The extra embryonic pro-definitive hematopoiesis launches in late E8 and the embryonic definitive one turns on at E10.5 indicated by the emergence of hemogenic endothelial cells on the inner wall of the extra embryonic arteries and the embryonic aorta. To study the roles of SCL protein isoforms in murine hematopoiesis, the SCL-large (SCL-L) isoform was selectively destroyed with the remaining SCL-small (SCL-S) isoform intact. It was demonstrated that SCL-S was specifically expressed in the hemogenic endothelial cells (HECs) and SCL-L was only detected in the dispersed cells after budding from HECs. The SCLΔ/Δ homozygous mutant embryos only survived to E10.5 with normal extra embryonic vessels and red blood cells. In wild-type mouse embryos, a layer of neatly aligned CD34+ and CD43+ cells appeared on the endothelial wall of the aorta of the E10.5 fetus. However, the cells at the same site expressed CD31 rather than CD34 and/or CD43 in the E10.5 SCLΔ/Δ embryo, indicating that only the endothelial lineage was developed. These results reveal that the SCL-S is sufficient to sustain the primitive hematopoiesis and SCL-L is necessary to launch the definitive hematopoiesis.

Developmental regulation of primitive erythropoiesis

“…Scl/Tal1 is a basic helix-loop-helix transcription factor and part of a multiprotein complex that activates transcription in hematopoietic lineage differentiation, maturation and leukemogenesis [46]. A recent study investigated the role of the Scl/Tal1 isoforms in murine primitive erythropoiesis [47]. Scl knockout mice die at E9.5 because of absent primitive erythropoiesis [42,43].…”

“…SCL isoforms with different hematopoietic lineage specificities have also been described in humans and mice [50,51]. Taking advantage of CRISPR/Cas9 technology, a mouse mutant was now created that carries an out of frame deletion in the fourth exon that is only used in the long Scl isoform [47]. The resulting homozygous embryos failed to form hemogenic endothelium, were highly anemic, and only survived to E10.5.…”