The Organization, Structure, and Role of Endothelial Cells During Organogenesis

Cellular crosstalk is essential for proper organogenesis. Although originally assumed to be simple conduits for blood, endothelial cells (ECs) actively coordinate organ development through communicating with nearby cell types to generate properly patterned tissues. Despite extensive studies detailing the signaling pathways important for organ development, little is known about how exactly ECs influence these processes. Furthermore, attempts to study ECs in this context have been hampered, in part, by an incomplete understanding of normal endothelial development in specific organs. Here, I characterized the organization, structure, and function of ECs during organ development in the kidney and lung. I first began with an in depth anatomical analysis of the kidney vasculature over the course of fetal development. I showed that the vasculature grows coordinately with the developing epithelium and stroma from the onset of kidney development and that it forms highly stereotyped structures around these other populations. I then carried out transcriptomic analysis of renal ECs and identified many novel EC-enriched genes expressed in the fetal kidney. From this analysis, I focused on the retinoic acid (RA)-catabolizing enzyme, Cyp26b1, which is enriched in ECs in both the kidney and the lung throughout development. Surprisingly, deletion of Cyp26b1 abrogated development of the lung, but not the kidney. Cyp26b1-null lungs exhibited defects in differentiation of the distal epithelium, leading to neonatal lethality. Transcriptomic and functional analyses suggested that the phenotype observed is due to RA-dependent and RA-independent mechanisms. On the other hand, the kidney appeared to be protected from loss of Cyp26b1 by upregulation of Dhrs3 to maintain normal RA levels. Bypassing Dhrs3 by exogenously administering RA interrupted kidney epithelial development only in mice lacking at least one allele of Cyp26b1. This body of work highlights the importance of EC-mediated cellular communication during development and identifies organ-specific mechanisms that regulate this crosstalk.