Differential gene expression analysis of 4days post fertilization (dpf) wildtype and flt1ka601zebrafish mutants to identify venous sprouting associated genes

Formation of organ-specific vasculatures requires cross-talk between developing tissue and specialized endothelial cells. Here we show how developing zebrafish spinal cord neurons coordinate vessel growth through balancing of neuron-derived Vegfaa, with neuronal sFlt1 restricting Vegfaa-Kdrl mediated angiogenesis at the neurovascular interface. Neuron-specific loss of flt1 or increased neuronal vegfaa expression promotes angiogenesis and peri-neural tube vascular network formation. Combining loss of neuronal flt1 with gain of vegfaa promotes sprout invasion into the neural tube. Upon loss of neuronal flt1, ectopic sprouts emanate from veins involving special angiogenic cell behaviors including nuclear positioning and a molecular signature distinct from primary artery or secondary venous sprouting. Manipulation of AV identity or Notch signaling established that ectopic sprouting in flt1 mutants requires venous endothelium. Conceptually our data suggest that spinal cord vascularization proceeds from veins involving two-tiered regulation of neuronal sFlt1 and Vegfaa via a novel sprouting mode. Overall design: Examination of wildtype (3 biological replicates, with two technical replicates each) and flt1ka601 homozygous mutants (3 biological replicates, with two technical replicates each)

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Wild R, Klems A, Takamiya M, Hayashi Y, Strähle U, Ando K, Mochizuki N, van Impel A, Schulte-Merker S, Krueger J, Preau L, le Noble F