Abstract
BackgroundDevelopment of neural and vascular systems displays astonishing similarities among vertebrates. This parallelism is under a precise control of complex guidance signals and neurovascular interactions. Previously, our group identified a highly conserved neural protein called thrombospondin type I domain containing 7A (THSD7A). Soluble THSD7A promoted and guided endothelial cell migration, tube formation and sprouting. In addition, we showed that thsd7a could be detected in the nervous system and was required for intersegmental vessels (ISV) patterning during zebrafish development. However, the exact origin of THSD7A and its effect on neurovascular interaction remains unclear.ResultsIn this study, we discovered that zebrafish thsd7a was expressed in the primary motor neurons. Knockdown of Thsd7a disrupted normal primary motor neuron formation and ISV sprouting in the Tg(kdr:EGFP/mnx1:TagRFP) double transgenic zebrafish. Interestingly, we found that Thsd7a morphants displayed distinct phenotypes that are very similar to the loss of Notch-delta like 4 (dll4) signaling. Transcript profiling further revealed that expression levels of notch1b and its downstream targets, vegfr2/3 and nrarpb, were down-regulated in the Thsd7a morphants. These data supported that zebrafish Thsd7a could regulate angiogenic sprouting via Notch-dll4 signaling during development.ConclusionsOur results suggested that motor neuron-derived Thsd7a plays a significant role in neurovascular interactions. Thsd7a could regulate ISV angiogenesis via Notch-dll4 signaling. Thus, Thsd7a is a potent angioneurin involved in the development of both neural and vascular systems.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-016-0277-9) contains supplementary material, which is available to authorized users.
Highlights
Development of neural and vascular systems displays astonishing similarities among vertebrates
We found that the spatiotemporal expression patterns of islet I and islet II transcripts were detected along the ventral edge of the neuron tube with discontinuous clusters, which were similar to that of thsd7a
Islet I is a middle primary motor neuron (MiP) and rostral primary motor neuron (RoP) marker, and islet II is a caudal primary motor neuron (CaP) marker. (Fig. 1b-c’). Both are specific markers for primary motor neurons [15]. These results indicated that zebrafish thsd7a was likely expressed in the primary motor neurons during development
Summary
Development of neural and vascular systems displays astonishing similarities among vertebrates. This parallelism is under a precise control of complex guidance signals and neurovascular interactions. Soluble THSD7A promoted and guided endothelial cell migration, tube formation and sprouting. Development of neural and vascular systems displays high similarity and this congruence is precisely regulated by complex neurovascular interactions and common guidance cues. We found a novel conserved protein, Thrombospondin type-I domain containing 7a (THSD7A), is highly expressed in human placental vasculature and umbilical vein endothelial cells (HUVECs). Overexpression of THSD7A in HUVECs inhibits directed cell migration and tube formation, while suppression of THSD7A generates the opposite effects. A soluble form of THSD7A increases the number of new vessel branching points, promotes HUVECs migration and tube formation
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