Abstract
Using the zebrafish model we describe a previously unrecognized requirement for the transcription factor gata4 controlling embryonic angiogenesis. The development of a vascular plexus in the embryonic tail, the caudal hematopoietic tissue (CHT), fails in embryos depleted of gata4. Rather than forming a normal vascular plexus, the CHT of gata4 morphants remains fused, and cells in the CHT express high levels of osteogenic markers ssp1 and runx1. Definitive progenitors emerge from the hemogenic aortic endothelium, but fail to colonize the poorly vascularized CHT. We also found abnormal patterns and levels for the chemokine sdf1a in gata4 morphants, which was found to be functionally relevant, since the embryos also show defects in development of the lateral line, a mechano-sensory organ system highly dependent on a gradient of sdf1a levels. Reduction of sdf1a levels was sufficient to rescue lateral line development, circulation, and CHT morphology. The result was surprising since neither gata4 nor sdf1a is obviously expressed in the CHT. Therefore, we generated transgenic fish that conditionally express a dominant-negative gata4 isoform, and determined that gata4 function is required during gastrulation, when it is co-expressed with sdf1a in lateral mesoderm. Our study shows that the gata4 gene regulates sdf1a levels during early embryogenesis, which impacts embryonic patterning and subsequently the development of the caudal vascular plexus.
Highlights
A characteristic feature of organ morphogenesis is the coordinated cell migration of groups of cells, resulting in the appropriate organ position, shape and size
The initiation of hematopoiesis appears normal in gata4 morphants based on in situ hybridization experiments to detect transcripts for the erythroid transcription factor gata1, and by imaging RFP+ cells in tg(gata1:dsRed) reporter fish (Fig. 1A–D)
In addition to its roles in cardiogenesis, gut organogenesis, and gonadal development, we discovered previously unknown functions for the transcription factor gata4 in two additional organ systems: the vascular system and the lateral line
Summary
A characteristic feature of organ morphogenesis is the coordinated cell migration of groups of cells, resulting in the appropriate organ position, shape and size. The gross phenotype of the mouse Gata mutant is defective embryonic folding, caused indirectly due to unknown alterations in extra-embryonic endoderm [3,4]. Conditional mouse mutants [5,6,7] and studies in zebrafish [8] defined functions for gata in early embryonic organ formation, including heart and liver. The morphogenetic genes that gata regulates remain largely unknown, they include cell cycle regulators [11] and signaling molecules including BMPs and WNT inhibitors [12], which can function by non-cell-autonomous mechanisms. Given the pleiotropic nature of the gata mutant phenotype, the question arises whether a common morphogenetic program controlled by gata functions in different organ systems, or if varied tissue-specific programs are downstream of gata to control development of distinct organ systems
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