Scl in the zebrafish: a simple (?) twist of fate

Comment on Patterson et al, page 3502

The transcription factor Scl plays an important role in the fate determination of definitive hematopoietic cells. A new report shows that Scl also plays a crucial role in the fate determination of the major vasculature in zebrafish embryos.

Scl (stem cell leukemia) has long been known as a pivotal transcription factor in the development of the hematopoietic system and particularly in determining hematopoietic fate. Mouse embryos lacking Scl exhibit complete anemia and embryonic lethality at embryonic day 9 (E9), thus precluding the study of definitive hematopoietic development.^1,2  Nonetheless, the endothelium of the major vasculature appears normal and only the remodeling of the vasculature was suggested to be disrupted due to the loss of Scl.³  However, initial findings in the zebrafish suggested a more important role for Scl in endothelial development.⁴  Ectopic expression of Scl in zebrafish embryos was shown to result in an overproduction of not only hematopoietic cells but also endothelial cells. This occurs at the expense of the paraxial mesoderm, suggesting that Scl could be a pivotal factor for the fate determination of both of these lineages. Indeed, in this issue of Blood, Patterson and colleagues now show, by using a morpholino approach, that knocked-down Scl synthesis results in the disruption of both of these cell lineages. Most dramatically, there is an absence of the dorsal aorta.

Why is endothelial fate affected in Scl-deficient zebrafish embryos but not in Scl^-/- mouse embryos? Is it a matter of developmental timing differences in hematopoietic and endothelial cell generation in the 2 organisms? Zebrafish embryos develop definitive blood and the dorsal aorta quickly and almost synchronously, whereas mouse embryos appear to first develop the dorsal aorta and then the definitive hematopoietic system (“She was born in spring but I was born too late,” Bob Dylan⁵ ). Or is it related to species differences in origins for endothelium? Fate mapping in the chick has shown 2 distinct endothelial lineages in the embryo, one of them (derived from splanchnic mesoderm) that contributes to the ventral wall of the dorsal aorta and has hemogenic potential and the other (derived from somatic mesoderm) that contributes to only the dorsal wall of the aorta.⁶  Here Patterson et al, while identifying many of the players in the genetic hierarchy affected by Scl, find one gene that is most interesting, the receptor tyrosine kinase gene, Flk-1. Flk-1, the receptor for vascular endothelial growth factor (VEGF), is downstream and perhaps a direct target of Scl. This is in contrast to mouse embryos, where Flk-1 expression precedes Scl expression. Thus, the sequence of commitment events to the hemangioblast, endothelial, and hematopoietic lineages differ between zebrafish and mouse. Thus, mapping genetic hierarchies can provide insight into fate determination events and lineage relationships through ontogeny.

These elegant studies further demonstrate the power of the zebrafish as a model for unraveling the genetic networks. In this study of the effects of Scl, a beautiful and comprehensive series of expression patterns (of blood- and endothelial-related genes) in the blood-forming areas of zebrafish embryos (morpholino-treated and normal) is presented. These patterns of expression fall into 4 categories that implicate direct versus nondirect regulation by Scl. With these extensive data, a model of molecular circuitry is beginning to emerge and the downstream effectors of Scl can be visualized in time and space. Eventually, these maps can be enlarged to reveal a complete genetic network of hematopoietic and endothelial development. ▪